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Graduate Student Literature Review: A scoping review on the impact of consumption of dairy products on phosphatidylcholine and lysophosphatidylcholine in circulation and the liver in human studies and animal models*

Open AccessPublished:November 15, 2022DOI:https://doi.org/10.3168/jds.2022-21938

      ABSTRACT

      Dairy consumption is inversely related to the risk of developing type 2 diabetes in epidemiological research. One proposed hypothesis is that phospholipid (PL) species associated with dairy consumption mediate this relationship. This scoping review aimed to identify the existing literature in animal and human trials investigating the impact of dairy products, including milk, yogurt, and cheese as well as dairy-derived PL supplementation on PL and its species in the circulation, summarizing the characteristics of these studies and identifying research gaps. A systematic search was conducted across 3 databases (PubMed, Scopus, and Web of Science) in March 2021. Of 2,427 identified references, 15 studies (7 humans and 8 animal studies) met the eligibility criteria and were included in the final narrative synthesis. The evidence base was heterogeneous, involving a variety of clinical and preclinical studies, metabolically healthy or obese/diabetic participants or animal models, and displayed mixed findings. Circulating postprandial concentrations of total PL were elevated acutely but unchanged after longer intervention with dairy products. The PL concentration remained stable even after a high dosage of milk supplemented with dairy-derived PL, which may be related to increased fecal excretion; however, certain phosphatidylcholine (PC) or lysophosphatidylcholine species were increased in circulation by interventions. These include several PC species with 32 to 38 total carbons in addition to the dairy biomarkers C15:0 and C17:0. The results of this scoping review demonstrate a small body of literature indicating that dairy products can influence blood concentrations of PC and lysophosphatidylcholine species in both rodents and humans without alteration of total PL and PC. There is a lack of well-designed trials in humans and animals that explore the potential differences between individual dairy foods on PL species. In addition, trials to understand the bioactive properties of PC and lysophosphatidylcholine species on cardiometabolic risk are needed.

      Key words

      INTRODUCTION

      Metabolic disorders such as insulin resistance, type 2 diabetes, metabolic dysfunction-associated fatty liver disease (also called nonalcoholic fatty liver disease), and dyslipidemia are related pathophysiological conditions in which normal metabolic processes of the body are disrupted (
      • O’Neill S.
      • O’Driscoll L.
      Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies.
      ). Investigations into identifying plasma metabolite signatures of obesity and metabolic dysfunction have uncovered crucial information on the molecular processes that cause cardiometabolic diseases. Strong evidence from MS-based lipidomic studies indicates that the pattern of circulating or tissue phospholipid (PL) is a unique biochemical signature associated with diagnosed metabolic disorders (
      • Cai T.
      • Yang F.
      Phospholipid and phospholipidomics in health and diseases.
      ;
      • Yin X.
      • Willinger C.M.
      • Keefe J.
      • Liu J.
      • Fernandez-Ortiz A.
      • Ibanez B.
      • Penalvo J.
      • Adourian A.
      • Chen G.
      • Corella D.
      • Pamplona R.
      • Portero-Otin M.
      • Jove M.
      • Courchesne P.
      • van Duijn C.M.
      • Fuster V.
      • Ordovas J.M.
      • Demirkan A.
      • Larson M.G.
      • Levy D.
      Lipidomic profiling identifies signatures of metabolic risk.
      ). Phospholipids, which have hydrophilic phosphate heads and hydrophobic lipid tails, are important molecules for signal transduction pathways and play important roles in membrane structure and cell division. Phosphatidylcholine (PC) is the most prevalent PL in mammalian cells. Lysophosphatidylcholine (LPC) is derived by hydrolytic cleavage of PC catalyzed by the phospholipase A2 enzymes (
      • Kita T.
      • Kume N.
      • Ishii K.
      • Horiuchi H.
      • Arai H.
      • Yokode M.
      Oxidized LDL and expression of monocyte adhesion molecules.
      ). Phospholipid panels captured using high-throughput technology have been widely used in epidemiological studies to improve prediction and better biological understanding of diseases. Disturbances in the proportion of PL subclasses and individual species may alter glucose and lipid homeostatic pathways leading to the development of glucose intolerance and to the progression of insulin resistance and type 2 diabetes (
      • Zeng Y.
      • Mtintsilana A.
      • Goedecke J.H.
      • Micklesfield L.K.
      • Olsson T.
      • Chorell E.
      Alterations in the metabolism of phospholipids, bile acids and branched-chain amino acids predicts development of type 2 diabetes in black South African women: A prospective cohort study.
      ). Phospholipid species can modulate the activity of the peroxisome proliferator-activated receptors and the production of eicosanoids and other lipid mediators that exacerbate obesity and low-grade inflammation (
      • Kim J.
      • Li Y.
      • Watkins B.A.
      Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity.
      ). Thus, some PL species have been identified as biomarkers of type 2 diabetes (
      • Hsu F.F.
      • Bohrer A.
      • Wohltmann M.
      • Ramanadham S.
      • Ma Z.
      • Yarasheski K.
      • Turk J.
      Electrospray ionization mass spectrometric analyses of changes in tissue phospholipid molecular species during the evolution of hyperlipidemia and hyperglycemia in Zucker diabetic fatty rats.
      ;
      • Guasch-Ferré M.
      • Hruby A.
      • Toledo E.
      • Clish C.B.
      • Martinez-Gonzalez M.A.
      • Salas-Salvado J.
      • Hu F.B.
      Metabolomics in prediabetes and diabetes: A systematic review and meta-analysis.
      ). For instance, reduced levels of LPC 18:2 are consistently associated with obesity, dysglycemia, insulin resistance, and type 2 diabetes, and have been proposed as a predictive biomarker for metabolic dysfunction (
      • Szymańska E.
      • Bouwman J.
      • Strassburg K.
      • Vervoort J.
      • Kangas A.J.
      • Soininen P.
      • Ala-Korpela M.
      • Westerhuis J.
      • van Duynhoven J.P.
      • Mela D.J.
      • Macdonald I.A.
      • Vreeken R.J.
      • Smilde A.K.
      • Jacobs D.M.
      Gender-dependent associations of metabolite profiles and body fat distribution in a healthy population with central obesity: Towards metabolomics diagnostics.
      ;
      • Wang-Sattler R.
      • Yu Z.
      • Herder C.
      • Messias A.C.
      • Floegel A.
      • He Y.
      • Heim K.
      • Campillos M.
      • Holzapfel C.
      • Thorand B.
      • Grallert H.
      • Xu T.
      • Bader E.
      • Huth C.
      • Mittelstrass K.
      • Doring A.
      • Meisinger C.
      • Gieger C.
      • Prehn C.
      • Roemisch-Margl W.
      • Carstensen M.
      • Xie L.
      • Yamanaka-Okumura H.
      • Xing G.
      • Ceglarek U.
      • Thiery J.
      • Giani G.
      • Lickert H.
      • Lin X.
      • Li Y.
      • Boeing H.
      • Joost H.G.
      • de Angelis M.H.
      • Rathmann W.
      • Suhre K.
      • Prokisch H.
      • Peters A.
      • Meitinger T.
      • Roden M.
      • Wichmann H.E.
      • Pischon T.
      • Adamski J.
      • Illig T.
      Novel biomarkers for pre-diabetes identified by metabolomics.
      ;
      • Ferrannini E.
      • Natali A.
      • Camastra S.
      • Nannipieri M.
      • Mari A.
      • Adam K.P.
      • Milburn M.V.
      • Kastenmuller G.
      • Adamski J.
      • Tuomi T.
      • Lyssenko V.
      • Groop L.
      • Gall W.E.
      Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance.
      ), whereas PC 38:3 has a positive association with obesity (
      • Yin X.
      • Willinger C.M.
      • Keefe J.
      • Liu J.
      • Fernandez-Ortiz A.
      • Ibanez B.
      • Penalvo J.
      • Adourian A.
      • Chen G.
      • Corella D.
      • Pamplona R.
      • Portero-Otin M.
      • Jove M.
      • Courchesne P.
      • van Duijn C.M.
      • Fuster V.
      • Ordovas J.M.
      • Demirkan A.
      • Larson M.G.
      • Levy D.
      Lipidomic profiling identifies signatures of metabolic risk.
      ). However, whether normalizing PL profiles is associated with improvements in outcomes is unclear.
      The liver plays a crucial role in lipid metabolism. Hepatic tissue is the primary site of PL production and metabolism (
      • Nguyen P.
      • Leray V.
      • Diez M.
      • Serisier S.
      • Le Bloc’h J.
      • Siliart B.
      • Dumon H.
      Liver lipid metabolism.
      ). Accumulating evidence supports the hypothesis that hepatic lipid deposition as triacylglycerides may not be inherently harmful in people with obesity and obesity-related diseases (
      • Alkhouri N.
      • Dixon L.J.
      • Feldstein A.E.
      Lipotoxicity in nonalcoholic fatty liver disease: Not all lipids are created equal.
      ;
      • Mashek D.G.
      Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD.
      ). However, as metabolic abnormalities progress, a more unhealthy hepatic lipid composition profile may lead to poorer metabolic health and a more aggressive fatty liver disease trajectory (
      • Musso G.
      • Cassader M.
      • Paschetta E.
      • Gambino R.
      Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis.
      ). In this context, bioactive lipid intermediates such as PC, LPC, and their species proposed to be linked to the development of hepatic lipotoxicity or insulin resistance, or both (
      • Gentile C.L.
      • Pagliassotti M.J.
      The role of fatty acids in the development and progression of nonalcoholic fatty liver disease.
      ;
      • Fridén M.
      • Rosqvist F.
      • Ahlström H.
      • Niessen H.G.
      • Schultheis C.
      • Hockings P.
      • Hulthe J.
      • Gummesson A.
      • Wanders A.
      • Rorsman F.
      • Risérus U.
      • Vessby J.
      Hepatic unsaturated fatty acids are linked to lower degree of fibrosis in non-alcoholic fatty liver disease.
      ). Therefore, rather than an absolute quantity, hepatic lipid composition may underpin hepatic and systemic metabolic dysfunction.
      Diet is a key modifiable risk factor for cardiometabolic diseases, and altering the dietary composition is an effective option to achieve and maintain healthy metabolic function (
      • Rychter A.M.
      • Ratajczak A.E.
      • Zawada A.
      • Dobrowolska A.
      • Krela-Kazmierczak I.
      Non-systematic review of diet and nutritional risk factors of cardiovascular disease in obesity.
      ). From a food group point of view, dairy products have beneficial effects on metabolic health (
      • Timon C.M.
      • O’Connor A.
      • Bhargava N.
      • Gibney E.R.
      • Feeney E.L.
      Dairy consumption and metabolic health.
      ;
      • Yuzbashian E.
      • Asghari G.
      • Mirmiran P.
      • Chan C.B.
      • Azizi F.
      Changes in dairy product consumption and subsequent type 2 diabetes among individuals with prediabetes: Tehran lipid and glucose study.
      ,
      • Yuzbashian E.
      • Nosrati-Oskouie M.
      • Asghari G.
      • Chan C.B.
      • Mirmiran P.
      • Azizi F.
      Associations of dairy intake with risk of incident metabolic syndrome in children and adolescents: Tehran lipid and glucose study.
      ) and are well recognized as nutrient-rich foods providing high-quality protein and calcium, among others (
      • Drewnowski A.
      • Fulgoni 3rd, V.
      Nutrient profiling of foods: Creating a nutrient-rich food index.
      ). However, dairy foods have a complex influence on metabolism because of differences in their industrial processing as well as the complex matrix of nutrients of each food (
      • Mozaffarian D.
      • Wu J.H.Y.
      Flavonoids, dairy foods, and cardiovascular and metabolic health: A review of emerging biologic pathways.
      ;
      • Astrup A.
      • Bertram H.C.
      • Bonjour J.P.
      • de Groot L.C.
      • de Oliveira Otto M.C.
      • Feeney E.L.
      • Garg M.L.
      • Givens I.
      • Kok F.J.
      • Krauss R.M.
      • Lamarche B.
      • Lecerf J.M.
      • Legrand P.
      • McKinley M.
      • Micha R.
      • Michalski M.C.
      • Mozaffarian D.
      • Soedamah-Muthu S.S.
      WHO draft guidelines on dietary saturated and trans fatty acids: Time for a new approach?.
      ). Several mechanisms have been evaluated to explain how dairy foods can influence metabolism and ameliorate metabolic risk factors (
      • Fernandez M.A.
      • Panahi S.
      • Daniel N.
      • Tremblay A.
      • Marette A.
      Yogurt and cardiometabolic diseases: A critical review of potential mechanisms.
      ;
      • Gille D.
      • Schmid A.
      • Walther B.
      • Vergeres G.
      Fermented food and non-communicable chronic diseases: A review.
      ;
      • Unger A.L.
      • Torres-Gonzalez M.
      • Kraft J.
      Dairy fat consumption and the risk of metabolic syndrome: An examination of the saturated fatty acids in dairy.
      ), but a full understanding remains incomplete.
      Milk and some by-products of dairy products are a considerable natural source of PL (
      • Pertiwi K.
      • Kupers L.K.
      • Wanders A.J.
      • de Goede J.
      • Zock P.L.
      • Geleijnse J.M.
      Associations of dairy and fiber intake with circulating odd-chain fatty acids in post-myocardial infarction patients.
      ;
      • Unger A.L.
      • Torres-Gonzalez M.
      • Kraft J.
      Dairy fat consumption and the risk of metabolic syndrome: An examination of the saturated fatty acids in dairy.
      ;
      • Timon C.M.
      • O’Connor A.
      • Bhargava N.
      • Gibney E.R.
      • Feeney E.L.
      Dairy consumption and metabolic health.
      ). Milk-based foods consist of many products with clear differences in nutritional profile and matrix. In particular, processing alters dairy lipid composition and distribution, especially PL, in the final matrix (
      • Pimentel L.
      • Gomes A.
      • Pintado M.
      • Rodríguez-Alcalá L.M.
      Isolation and analysis of phospholipids in dairy foods.
      ). Compared with cows' raw milk, cream, butter, and buttermilk contain 2 to 5-fold more PL by weight, but even skim milk retains PL comparable to whole milk, similar to hard cheeses and yogurt (
      • Pimentel L.
      • Gomes A.
      • Pintado M.
      • Rodríguez-Alcalá L.M.
      Isolation and analysis of phospholipids in dairy foods.
      ). However, cream and butter are naturally high in saturated fats and therefore have been limited by dietary guidelines to support a healthy diet (
      • MyPlate
      Dairy. Accessed Nov. 2, 2022.
      ). On the other hand, milk, yogurt, and cheese have been recommended by
      • MyPlate
      Dairy. Accessed Nov. 2, 2022.
      as dairy products and account for 75 to 95% of total daily milk-based product intake in various populations (
      • Hjartåker A.
      • Lagiou A.
      • Slimani N.
      • Lund E.
      • Chirlaque M.
      • Vasilopoulou E.
      • Zavitsanos X.
      • Berrino F.
      • Sacerdote C.
      • Ocké M.C.
      • Peeters P.H.M.
      • Engeset D.
      • Skeie G.
      • Aller A.
      • Amiano P.
      • Berglund G.
      • Nilsson S.
      • McTaggart A.
      • Spencer E.A.
      • Overvad K.
      • Tjønneland A.
      • Clavel-Chapelon F.
      • Linseisen J.
      • Schulz M.
      • Hermon B.
      • Riboli E.
      Consumption of dairy products in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: Data from 35955 24-hour dietary recalls in 10 European countries.
      ;
      • Wang Y.
      • Li S.
      Worldwide trends in dairy production and consumption and calcium intake: Is promoting consumption of dairy products a sustainable solution for inadequate calcium intake?.
      ;
      • Rabiei S.
      • Zahedi M.
      • Abtahi M.
      • Doustmohammadian A.
      • Dadkhah M.
      • Zoghi T.
      • Zadeh N.S.
      • Khosroushahi I.
      • Hajigholam-saryazdi M.
      Consumption of milk and dairy products in Iranian population; barriers and facilitators.
      ). Thus, milk, cheese, and yogurt contribute the majority of dairy-derived PL in most diets. A hypothesis is proposed that the beneficial effects of dairy products on metabolic health may pertain to normalizing PL metabolism, mainly compensating circulating species of PC and LPC. Observational studies investigating modifications of the plasma metabolome associated with dairy consumption in individuals with metabolic disorders support this hypothesis (
      • Nestel P.J.
      • Straznicky N.
      • Mellett N.A.
      • Wong G.
      • De Souza D.P.
      • Tull D.L.
      • Barlow C.K.
      • Grima M.T.
      • Meikle P.J.
      Specific plasma lipid classes and phospholipid fatty acids indicative of dairy food consumption associate with insulin sensitivity.
      ;
      • Pertiwi K.
      • Kupers L.K.
      • Wanders A.J.
      • de Goede J.
      • Zock P.L.
      • Geleijnse J.M.
      Associations of dairy and fiber intake with circulating odd-chain fatty acids in post-myocardial infarction patients.
      ;
      • Santaren I.D.
      • Bazinet R.P.
      • Liu Z.
      • Johnston L.W.
      • Sievenpiper J.L.
      • Giacca A.
      • Retnakaran R.
      • Harris S.B.
      • Zinman B.
      • Hanley A.J.
      The distribution of fatty acid biomarkers of dairy intake across serum lipid fractions: The prospective metabolism and islet cell evaluation (PROMISE).
      ).
      However, the effect of various kinds of dairy products or supplementation with dairy-derived PL on circulating PL subclasses and their potential relation with cardiometabolic health are still generally unknown. A more explicit description of the evidence base on human and animal studies is required to understand how dairy products or dairy-derived PL may alter the total or individual PL species in the circulation and their consentation in the liver. Therefore, we conducted a scoping review of the existing literature of both animal and human trials to synthesize the available data on the influence of dairy products and dairy-derived PL on circulating PL, its subgroups, and species to better understand their metabolic effects and, more specifically, their impact on cardiometabolic health. The specific research questions were as follows: (1) In adults, what is the impact of increasing dairy PL on circulating PL, PC, or LPC? (2) In rodent models, what is the impact of increasing dairy PL on circulating or hepatic PL, PC, or LPC? We also provide an overview of available data on the cardiometabolic risk factors in the included studies. In this context, human intervention trials providing a diet modifying the amount of dairy PL (using dairy products with or without PL enrichment) were reviewed to provide evidence of the impact of dairy PL on circulating PL subclasses and individual species concentrations. Animal experiments were included to provide insights into the mechanisms of action of dairy on circulating PL. The effects of interventions on liver PL observed in animal studies were also analyzed as a secondary outcome of interest. The knowledge gap and research needs were also identified, and a theoretical basis for future research and practical applications were provided.

      METHODS

      Search Strategy

      Three online databases, including PubMed ( https://pubmed.ncbi.nlm.nih.gov/ ), Scopus ( https://www.scopus.com ), and Web of Science ( https://www.webofscience.com ), were searched in March 2021 to find relevant studies published between January 2000 to January 2021. Search terms were determined using the MeSH database ( https://www.ncbi.nlm.nih.gov/mesh/ ) and relevant reviews. In addition to terms identified in the MeSH database, the following search terms were used to define specific search syntax (Supplemental File S1; https://figshare.com/articles/online_resource/Supplementary_docx/21397164 ;
      • Yuzbashian E.
      • Moftah S.
      • Chan C.B.
      Supplementary.docx. figshare.
      ) for each database: “dairy, milk, yogurt, and cheese” (
      • MyPlate
      Dairy. Accessed Nov. 2, 2022.
      ) combined with “phospholipid, phosphatidylcholine, and lysophosphatidylcholine.” After a careful manual search of all included studies' reference lists, additional studies were added. We selected studies that were conducted on either humans or animals. A summary of the review and the reasons for excluding studies are presented in the PRISMA flowchart (Figure 1).
      Figure thumbnail gr1
      Figure 1Flowchart of the study selection process in systematic literature review, according to PRISMA guidelines.

      Eligibility Criteria

      Studies included were interventional trials (animal and human) that investigated the effect of total or individual dairy products on the circulating or liver content of PL, PC, and LPC. Studies assessing dairy products based on MyPlate definition, including milk, skim, low-fat or full-fat milk, yogurt, and cheese custard, were included, but studies evaluating ice confections, ice creams, cream, sour cream, or butter were excluded. We also included studies that administered dairy-derived PL, for example, milk, or other types of dairy food enriched with dairy-derived PL. Studies that supplemented participants with PL from other sources were excluded. The outcome measures of interest were serum/plasma concentration and liver content of PL, PC, LPC, and their species. We excluded in vitro studies and narrative, nonsystematic reviews, conference abstracts, as well as those not published in English.

      Selection Process

      Relevant studies were stored in EndNote, and the title/abstract screening process initiated after removing duplicate articles. The full texts of the remaining studies were read to check inclusion and exclusion criteria, detailed above.

      Data Charting

      Charting forms were developed separately for human and animal studies, and 1 reviewer (E.Y.) charted information. The second reviewer (S.M.) checked all of the records. From each human study, the following data were charted: authors' names, publication year, aim, sample size, age, study design, study duration, participants' health conditions, results related to PL and its subclasses, and the main metabolic outcome of the study. The charted data for animal studies were authors' names, publication year, aim, animal species, sex, age, number of animals in intervention groups and control groups, intervention characteristics, and main results, including metabolic outcomes. In the case of missing data or unclear pieces of information, it was considered that the authors did not report such variables.

      Risk of Bias

      The risk of bias (RoB) in human randomized trials was assessed using the revised Cochrane's Risk of Bias (RoB2) assessment tools for randomized trials (
      • Higgins J.P.T.
      • Sterne J.A.C.
      • Savovic J.
      • Page M.J.
      • Hróbjartsson A.
      • Boutron I.
      • Reeves B.
      • Eldridge S.
      A revised tool for assessing risk of bias in randomized trials.
      ). For animal studies, SYRCLE's RoB tool was used to assess the RoB (
      • Hooijmans C.R.
      • Rovers M.M.
      • de Vries R.B.
      • Leenaars M.
      • Ritskes-Hoitinga M.
      • Langendam M.W.
      SYRCLE’s risk of bias tool for animal studies.
      ). Both RoB results had been visualized by robvis (
      • McGuinness L.A.
      • Higgins J.P.T.
      Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments.
      ). Both tools assess the studies' methodological quality by evaluating selection, performance, detection, attrition, reporting, or other bias. Evaluation of potential bias for each included study was done by 1 reviewer (E.Y.) and checked by a second (C.B.C.).

      Summarization of Data

      The data on the response of PL, PC, LPC, and their species to the dairy consumption were summarized as significantly increased, decreased, or not changed by the intervention(s). We grouped the included studies by health conditions of the participants/animal models and duration of the intervention. The results were synthesized as a narrative summary of human and animal studies separately.

      RESULTS

      Overview of Publications

      In this review, 2,427 articles were identified and screened after removing duplicates. After evaluation of the titles and abstracts, 133 papers were selected for full-text assessment, of which 15 studies were identified that met the inclusion criteria. The citation lists of all included references were then reviewed to identify any additional relevant articles. Studies were classified according to their type, resulting in 7 human trials (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ;
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ;
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ) and 8 animal studies (
      • Ramaprasad T.R.
      • Mohan K.
      • Sambaiah J.
      • Prakash
      • Lokesh B.
      Effect of dietary milk cream and egg yolk fat on serum and liver lipid profile in rats.
      ;
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ;
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ;
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ;
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ).
      All human studies were randomized trials, either parallel (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ;
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ;
      • Norris G.H.
      • Porter C.M.
      • Jiang C.
      • Millar C.L.
      • Blesso C.N.
      Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice.
      ) or crossover design (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ) with duration ranging from 1 to 4 h to 12 wk. Participant mean ages ranged from 25 to 63 yr. The participants of 3 studies were apparently healthy, or there was no restriction on the inclusion criteria (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ), whereas others selected individuals with high risk for cardiovascular disease (
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ), overweight, or obesity (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ;
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ;
      • Norris G.H.
      • Porter C.M.
      • Jiang C.
      • Millar C.L.
      • Blesso C.N.
      Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice.
      ). Of 7 human studies, only 4 considered plasma concentration of PL as the primary outcome (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ). Interventions varied from milk supplemented with 2, 3, or 6 g of milk-derived PL (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ) and manipulation of dairy product consumption in the regular daily diet of participants (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ;
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ). A summary of the included studies' details and findings are presented in Table 1, sorted by year of publication.
      Table 1Summary of the human interventional studies that evaluated the effects of dairy on phospholipid and its subclass concentrations
      Author, yearParticipant
      CVD = cardiovascular disease.
      (age/n/risk factors/gender)
      Design
      RCT = randomized controlled trial.
      Intervention
      HF = high-fat; LF = low-fat; PL = phospholipid; PS = plant sterols; TFA = trans fatty acids; IP-TFA = industrial produced trans fatty acids; R-TFA = ruminant trans fatty acids; LCD = low calorie diet.
      Duration (wk)Main result
      PC = phosphatidylcholine; LPC = lysophosphatidylcholine; up arrows = increased; down arrows = decreased.
      Outcome of interest
      GGT = γ-glutamyl transferase; TC = total cholesterol; BMI = body mass index; CRP = C-reactive protein.
      Markey et al. (2017)25–70 yr/54/high risk for CVD/bothCrossover RCTIsocaloric HF diet (38% total energy) with SFA-reduced, MUFA-enriched dairy products (modified) or regular dairy (control)12Modified vs. control: ↓ PC species including 14:0, 15:0, 17:0, 20:3, total SFA ↑ PC species including 16:0, 18:1, total MUFAThere was no significant treatment effect for anthropometric measurements.
      Weiland et al. (2016)
       Trial 150–76 yr/62/overweight or obese/menDouble-blind, parallel-group RCTParticipants consumed 200 mL/d LF milk enriched with 2 g of milk-PL (PL group) or 200 mL/d of milk enriched with 2 g of milk fat8Plasma total PL not affected by the intervention (1.97 ± 0.32 vs. 1.93 ± 0.37)GGT activity decreased.
       Trial 250–76 yr/57/overweight or obese/menDouble-blind, parallel-group RCTParticipants consumed 250 mL/d of LF milk enriched with 3 g of milk-PL (PL group) or 250 mL/d of milk enriched with 2.8 g of soy-PL7Plasma total PL not affected by the intervention (2.27 ± 0.41 vs. 2.22 ± 0.35)GGT activity slightly decreased.
      Meikle et al. (2015)40–46 yr/16/healthy/menCrossover RCTParticipant consumed a breakfast containing HF dairy products or a breakfast containing soy oil-based foodsPostprandial (1–4 h after eating)Dairy meal vs. baseline: No change in total LPC ↑ plasma total PC ↑ PC species including 28:0, 29:0, 30:0, 32:0, 32:1, 32:2, 32:3, 33:2, 33:3, 34:2, 34:3, 35:2, 35:3, 36:1, 36:3, 36:5, 36:6, 38:3, and LPC species including 18:3, 24:0 ↓LPC species including 20:1, 22:5 Dairy meal vs. soy meal: ↑ PC and PC species with odd-chain FA (15:0 and 17:0) and PC species including 29:0, 28:0, 30:0, 31:0, 32:0, 32:1, 35:1, 36:3, 36:4, 36:5, 38:3, 38:5, 38:6, 40:5, and 40:6No metabolic parameters were measured.
      Keller et al. (2014)Adults/39/atopic dermatitis-metabolically healthy/bothDouble-blind, crossover RCTParticipants consumed 250 mL/d of LF milk enriched with 3 g of milk-PL (PL group) or 250 mL/d of whole milk (control)6Plasma total PL (2.13 ± 0.36 vs. 2.09 ± 0.29 in PL group and 2.12 ± 0.33 vs. 2.09 ± 0.35 in control), PC, and LPC not affected by the interventionThere was no treatment effect on lipid profile and inflammation parameters.
      Keller et al. (2013)Adults/14/healthy/womenOpen-label, crossover RCTParticipants consumed LF milk enriched with 3 g of milk-PL (low-PL group) or LF milk enriched with 6 g of milk-PL (high-PL group) or LF milk enriched with 2 g of plant sterol (PS-PL group)10 dPlasma total PL (2.27 ± 0.44 vs. 2.35 ± 0.36 vs. 2.29 ± 0.41) and PC not affected by the interventions PS-PL group vs. baseline and low-PL group: ↑ LPCTC in plasma was lower after low-PL in comparison with baseline. TC and LDL cholesterol rose significantly compared with low-PL PS-PL, resulted in lower LDL cholesterol compared with high PL.
      Tardy et al. (2009)18–50 yr/63/abdominal obesity/womenDouble-blind, parallel-group RCTParticipants consumed industrial-sourced TFA lipids containing hydrogenated vegetable oil (IP-TFA diet) or ruminant TFA–vaccenic acid-rich milk fat (R-TFA diet) or low-TFA diet: palm oil with hydrogenated sunflower oil (low-TFA)4Plasma total PL not affected by the intervention R-TFA vs. baseline: ↑ 18:1trans-11 and PL content in total n-3 PUFA ↓ PL content in total SFA and n-6 PUFAThere was no treatment effect for fasting glycemia, insulinemia, lipid profile, and markers of liver function and inflammation.
      Hlavatý et al. (2008)Adults/40/obese/womenParallel-group RCTParticipants receive 1 serving regular-fat yogurt (LCD); prescribed caloric intake was 60% of energy expenditure3LCD vs. baseline: ↑ PC species including 16:0, 18:1n-7, ↓ PC species including 14:0, 18:0, 20:2n-6, 20:3n-6, 20:4n-6, 20:5n-3, total SFABMI, LDL cholesterol, and CRP were lower after a yogurt in comparison with baseline.
      1 CVD = cardiovascular disease.
      2 RCT = randomized controlled trial.
      3 HF = high-fat; LF = low-fat; PL = phospholipid; PS = plant sterols; TFA = trans fatty acids; IP-TFA = industrial produced trans fatty acids; R-TFA = ruminant trans fatty acids; LCD = low calorie diet.
      4 PC = phosphatidylcholine; LPC = lysophosphatidylcholine; up arrows = increased; down arrows = decreased.
      5 GGT = γ-glutamyl transferase; TC = total cholesterol; BMI = body mass index; CRP = C-reactive protein.
      Most animal studies (n = 7) were conducted in mice (
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ;
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ;
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ;
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ) except for 2 studies, which selected rats (
      • Ramaprasad T.R.
      • Mohan K.
      • Sambaiah J.
      • Prakash
      • Lokesh B.
      Effect of dietary milk cream and egg yolk fat on serum and liver lipid profile in rats.
      ,
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ; Table 2). Interventions included milk supplemented with milk-derived PL (
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ;
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ;
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ), cheese (
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ), MUFA-enriched dairy foods (
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ), and 1 that used milk fat (
      • Ramaprasad T.R.
      • Mohan K.
      • Sambaiah J.
      • Prakash
      • Lokesh B.
      Effect of dietary milk cream and egg yolk fat on serum and liver lipid profile in rats.
      ). Only 2 out of 7 studies considered PL or its subclasses as a primary outcome (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ).
      Table 2Summary of the animal studies that evaluated the effect of dairy on phospholipid and its subclass concentrations
      Author, yearModelIntervention
      HFLP = high-fat diet plus phospholipid; HF = high-fat; LF = low-fat; PL = phospholipid; GG = gangliosides; REG = regular; NPL = standard (normal) diet with phospholipid; N = normal diet; GNO = groundnut oil.
      Duration (wk)Main result
      PC = phosphatidylcholine; LPC = lysophosphatidylcholine; up arrows = increased; down arrows = decreased.
      Millar et al. (2020)Mice LDLr−/− C57BL/6JHFPL1: HF diet + milk-PL 1% by wt HFPL2: HF diet + milk-PL 2% by wt Control: HF diet14No change in PC and PL of liver
      Zhou and Ward (2019)Mice C57BL/6J ob/obGG: standard diet + milk gangliosides at 0.2 g/kg of diet PL: standard diet + with milk-PL at 10 g/kg of diet Control: standard diet2↑ Total serum PL in the PL group compared with the GG and control groups No change in PC and PL of liver
      Hanning et al. (2019)Rat Sprague DawleyREG: HF diet + regular-fat cheese diet Low: HF diet + LF cheese diet HF diet: HF diet Control: LF diet8Low vs. HF diet: ↑ LPC species including 14:0, 16:0, 16:1, 17:0, 18:1, 20:3, and 20:4 and PC species including 30:0, 32:2, 34:1, 34:3, 34:4, 36:3, 36:5, 38:3, 38:0 REG vs. HF diet: ↑ LPC species including 14:0, 16:0, 16:1, 17:0, 18:1, 20:3, and 24:0 and PC species including 30:0, 32:1, 32:2, 34:1, 34:3, 34:4, 36:3, 36:5, 38:3, 38:0, 42:0 REG vs. low: ↑ PC species including 30:0 and LPC species including 14:0 ↓ PC species including 32:1, 34:3, 30:0, 36:5, 42:0, LPC species including 16:0 Plasma and liver total PL, PC, LPC were not affected by intervention
      Milard et al. (2019)Mice C57Bl/6HFPL1: HF diet + milk-PL 1.9% (wt/wt) HFPL2: HF diet + milk-PL 3.8% (wt/wt) HF: HF diet LF: LF diet8Liver content in PL, total SFA, MUFA, and PUFA did not differ among groups Liver: HFPL1 vs. HF: ↑ PL species including 20:2, 23:0, 24:0 HFPL2 vs. HF: ↑ PL species including 20:2, 23:0, and 24:0 ↓ PL species including 18:1(n-7) HFPL2 vs. HFPL1: ↑ PL species including 20:2, 23:0 ↓ PL species including 18:1(n-7) HFPL1 vs. LF: ↑ PL species including 18:1(n-9), 22:0, 20:3(n-3), 20:4(n-6), 23:0, 24:0 ↓ PL species including 14:0, 15:0, 16:1, 18:1(n-7), 18:2(n-6), 20:1, 20:5, 24:1 HFPL2 vs. LF: ↑PL species including 18:1(n-9), 22:0, 20:4, 23:0, 24:0 ↓PL species including 14:0, 15:0, 16:1, 18:1(n-7), 18:2 (n-6), 20:1, 20:5, 24:1
      Kamili et al. (2010)Mice C57BL/6HFPL: HF diet + milk-PL Control: HF diet8Plasma PL was not affected by the intervention HFPL vs. control: Feces: ↑ all PL species and PC Plasma: ↑ PC species including 32:1, 34:1, 32:0, 34:0 Liver: total PL was not affected by the intervention ↓ total PC, PC species including 34:1, PC 34:2, PC 38:6; PC 36:3
      Wat et al. (2009)Mice C57BL/6HFPL: HF diet + milk-PL 2.5% (wt/wt) HF diet: HF diet NPL: standard diet + milk-PL 2.5% (wt/wt) N: normal diet8HFPL vs. HF diet Liver: ↓ PL Serum: ↓ PL
      Higuchi et al. (2008)Mice Crlj:CD-1 (ICR)10% yogurt 30% yogurt Control12Plasma: 10% yogurt and 30% yogurt had lower PL concentrations than control group No change in PC and PL of liver
      Ramaprasad et al. (2003)Rats wistarStandard diet + milk fat GNO: standard diet + groundnut oil High-cholesterol diet + milk fat GNO: high-cholesterol diet + groundnut oil8Standard diet Plasma: ↑ PL in milk fat Liver: no difference between groups Cholesterol-enriched diet Plasma: no difference between groups Liver: no difference between groups
      1 HFLP = high-fat diet plus phospholipid; HF = high-fat; LF = low-fat; PL = phospholipid; GG = gangliosides; REG = regular; NPL = standard (normal) diet with phospholipid; N = normal diet; GNO = groundnut oil.
      2 PC = phosphatidylcholine; LPC = lysophosphatidylcholine; up arrows = increased; down arrows = decreased.

      Study Quality and RoB

      The results of the RoB evaluation for human and animal studies are shown in Figure 2, Figure 3, respectively. Three human studies were assigned high RoB (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ;
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ;
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ) with the main reason being a lack of information on randomization, concealment methods, and blinding of participants and investigators, which is a limitation of most nutrition interventions. The results for RoB were assessed as low for 2 studies (
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ) and as some concerns in 2 randomized controlled trials (RCT;
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ) because of the randomization method.
      Figure thumbnail gr2
      Figure 2Risk of bias in included human studies. Review authors' judgments about each risk of bias item for each included study. The domains of risk are shown for each study. Color coding is used to depict a 3-point scale for bias. Green (+) reflects a low risk of bias, red (X) a high risk of bias, and yellow (-) an unclear risk of bias.
      Figure thumbnail gr3
      Figure 3Risk of bias in included animal studies. Review authors' judgments about each risk of bias item for each included study. The domains of risk are shown for each study. Color coding is used to depict a 3-point scale for bias. Green (+) reflects a low risk of bias, red (X) a high risk of bias, and yellow (-) an unclear risk of bias.
      The ARRIVE guidelines for reporting animal studies ( https://arriveguidelines.org ) have not been as widely adopted as the CONSORT guidelines for reporting RCT. Thus, assessing their RoB based on methodological quality is more difficult. Two studies (
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ;
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ) did not report the randomized allocation of animals, leading to high RoB, whereas other authors (
      • Ramaprasad T.R.
      • Mohan K.
      • Sambaiah J.
      • Prakash
      • Lokesh B.
      Effect of dietary milk cream and egg yolk fat on serum and liver lipid profile in rats.
      ;
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ;
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ) stated that the allocation was randomized, but procedural details were not reported. Baseline characteristics between groups were poorly reported; therefore, we selected the initially reported BW to evaluate RoB. Only 4 studies received low RoB (
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ;
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ;
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ) based on no BW differences between groups at baseline, whereas the rest were unclear. None of the studies reported data on blinding of caregivers or investigators or on the random selection of animals for outcome assessment, leading to the assignment of unclear RoB. No blinding of the outcome assessor was reported; however, the outcome of interest (PL) was an objective measurement less subject to bias than subjective measures. Regarding attrition bias, only 1 study reported that a considerable number of animals died during the study (
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ); for other studies, information about the animal loss was adequate, and a similar number of analyzed animals in each group of the studies was reported. On this basis, all studies were assigned a low RoB for attrition. The assessment of PL and its subclasses was the primary outcome of 2 included studies, so the RoB for this domain was judged as low (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ).

      Human Studies

      In Table 1, the main study characteristics and results of the effect of dairy consumption on PL concentration are summarized. Overall, circulating PL ranged from 1.93 to 2.23 mmol/L in all human subjects, regardless of their health. In the following sections, the studies are described in detail based on the initial health of participants.

      Healthy Participants

      Only 2 studies focused on healthy participants. One trial evaluated the acute impact of dairy products on circulating postprandial PL. Compared with soy-based foods, a breakfast meal comprised of high-fat (HF) dairy foods (consisting of cheddar cheese, butter, and extra creamy whole milk) increased postprandial total plasma PC and PC containing dairy-derived fatty acids C15:0 and C17:0, but not LPC or circulating triglycerides (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ). After the dairy meal, postprandial plasma PC species including 29:0, 33:2, 33:3, 35:2, 35:3, 28:0, 30:0, 32:0, 32:1, 32:2, 32:3, 34:2, 34:3, 36:1, 36:3, 36:5, 36:6, 38:3, and LPC 18:3 and 24:0 increased significantly. However, plasma LPC species including 20:1, 22:5, and 18:1 decreased after a HF dairy meal (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ). In healthy women, a short-term (10 d) intervention with milk enriched with milk-derived PL of 3- or 6-g dose had no effect on plasma PL, PC, and LPC (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ). Decreased high-density lipoprotein cholesterol compared with baseline after 3 g of milk-PL intervention was noted, but no correlations with plasma PL were presented. Interestingly, measurements in feces indicated a slight milk-PL dose-dependent increase in PL excretion (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ). Similarly, a randomized crossover trial with 6-wk intervention arms found no effect of consuming LF milk supplemented with 3 g of milk-PL compared with whole milk on either plasma total PL, PC, or LPC or on lipid profile or inflammatory markers (
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ). However individual PC and LPC species were not reported in the latter 2 studies (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ).

      Participants with Cardiometabolic Risk Factors

      No acute studies were identified. In women with obesity, a 3-wk intervention with regular yogurt showed that, compared with baseline, PC 16:0 and 18:1n-7 increased, whereas PC species including 14:0, 18:0, 20:2n-6, 20:3n-6, 20:4n-6, 20:5n-3 and total SFA decreased, compared with the baseline valuses without alterations in total PL (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ). Participants' body mass index, LDL cholesterol, and C-reactive protein were lower after yogurt provision in comparison with baseline; however, this result was confounded by prescribed 30% reduction in energy intake as part of the intervention.
      The impact of dairy products on circulating PL was consistent in 4 studies with interventions ≥4 wk. Three studies (2 trials) were conducted on people with obesity (
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      ;
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ), with 1 considering additional cardiovascular risk factors (
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ). One of the parallel-arm RCT (using milk-PL enriched LF milk) found no effect on total plasma PL (
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ). This study also found no intervention effect on most metabolic outcomes. However, Weiland et al. found either increased gamma-glutamyl transferase in the milk fat control group (trial 1) or reduced gamma-glutamyl transferase in the PL group (compared with a soy-PL control, trial 2), which was interpreted as a benefit of milk-PL on fatty liver (
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ).
      Dairy-derived biomarkers PL 15:0 and 17:0 in the blood can indicate intervention compliance (
      • Pranger I.G.
      • Corpeleijn E.
      • Muskiet F.A.J.
      • Kema I.P.
      • Singh-Povel C.
      • Bakker S.J.L.
      Circulating fatty acids as biomarkers of dairy fat intake: Data from the lifelines biobank and cohort study.
      ;
      • Azab S.M.
      • de Souza R.J.
      • Teo K.K.
      • Anand S.S.
      • Williams N.C.
      • Holzschuher J.
      • McGlory C.
      • Philips S.M.
      • Britz-McKibbin P.
      Serum nonesterified fatty acids have utility as dietary biomarkers of fat intake from fish, fish oil, and dairy in women.
      ). Two trials examined the incorporation of specific fatty acids into the plasma PL fraction.
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      found that provision of ruminant trans fats increased their abundance in circulating PL while also increasing total MUFA and reducing total SFA and PUFA in PL.
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      likewise found that feeding dairy enriched in MUFA and depleted in SFA (dcreased amount of PC 15:0 and 17:0) led to a similar pattern in fatty acids incorporated into plasma PL. Thus, although most studies show null effects on total PL, differences can be observed when PL species are quantified. In addition to being a measure of compliance when C15:0 and C17:0 are measured, it is possible that certain species may exert biological activities. However,
      • Tardy A.L.
      • Lambert-Porcheron S.
      • Malpuech-Brugere C.
      • Giraudet C.
      • Rigaudiere J.P.
      • Laillet B.
      • Leruyet P.
      • Peyraud J.L.
      • Boirie Y.
      • Laville M.
      • Michalski M.C.
      • Chardigny J.M.
      • Morio B.
      Dairy and industrial sources of trans fat do not impair peripheral insulin sensitivity in overweight women.
      did not find differences in BW or metabolic outcomes in women with abdominal obesity, and
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      performed no metabolic measurements.

      Animal Studies

      Eight studies assessed the effect of dairy intake on PL metabolism in animals, with 6 employing obese rodent models or HF background diet to induce obesity. Regarding total plasma PL in obese mice and rats,
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      and
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      found no difference, whereas
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      reported an increase and
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      reported a decrease after dairy consumption.
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      was the only study to use cheese, whereas the other groups employed milk-PL or milk gangliosides; in fact, all studies intervened for 8 wk. Total hepatic PL was likewise unchanged by the intervention in 5 studies (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ;
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ;
      • Millar C.L.
      • Jiang C.
      • Norris G.H.
      • Garcia C.
      • Seibel S.
      • Anto L.
      • Lee J.Y.
      • Blesso C.N.
      Cow’s milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.
      ), with
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      noting a decrease. Interestingly, fecal PL excretion increased by 2.8-fold in the latter study (
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ) and
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      also noted increased excretion of PL. On a standard LF diet background, enrichment with milk-PL had no effect on plasma or hepatic PL in mice with a mutation of the obese (ob) gene encoding leptin (
      • Zhou A.L.
      • Ward R.E.
      Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity.
      ).
      In non-obese rodents, PL increased in plasma but not liver in a rat study using standard LF diet plus milk fat compared with LF control diet (
      • Ramaprasad T.R.
      • Mohan K.
      • Sambaiah J.
      • Prakash
      • Lokesh B.
      Effect of dietary milk cream and egg yolk fat on serum and liver lipid profile in rats.
      ). However, PL concentration and liver content were stable after adding a certain amount of PL in their standard diet (
      • Wat E.
      • Tandy S.
      • Kapera E.
      • Kamili A.
      • Chung R.W.
      • Brown A.
      • Rowney M.
      • Cohn J.S.
      Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet.
      ). Conversely, on a high-cholesterol diet background, milk fat had no effect on PL in plasma or liver (
      • Higuchi T.
      • Shirai N.
      • Suzuki H.
      • Kawashima M.
      • Tamura Y.
      Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.
      ). Even in the absence of effects on total PL, multiple 8-week trials in obese rodent models that measured PL species reported alterations (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ;
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ). A combination of HF diet with 1.9 or 3.8% (wt/wt) milk-PL increased hepatic PL 20:2, 23:0, and 24:0 compared with the HF diet group (
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ), but plasma concentrations were not reported. Plasma PC species 32:1, 34:1, 32:0, and 34:0 increased, but liver total PC and species 34:1, 34:2, 38:6; and 36:3 decreased (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ). In a study in rats, several PC and LPC species decreased in the HF diet group compared with the LF diet. However, intervention with regular- or reduced-fat cheese increased their concentration toward normal. For example, HF diet-induced reductions in LPC species such as 14:0, 16:0, 16:1, 17:0, 18:1, and 20:3 and PC species including 30:0, 34:1, 34:3, 34:4, 36:3, 36:5, and 38:3 were increased to the LF diet values by the cheese interventions (
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ).

      DISCUSSION

      This scoping review synthesized the research on the effects of dairy intake or milk-PL on circulating PL and its subclasses, including LPC and PC. Although the design and quality of included intervention studies were heterogeneous, and some were not specifically designed to investigate the effects of dairy intake, the findings were relatively consistent. The main finding is that, in contrast to acute intervention, chronic human studies 10 d to 12 wk long generally demonstrate that total circulating PL, PC, and LPC are not affected by intervention with dairy products, remaining stable even after a high dosage of milk-PL. However, the serum concentration of PC and LPC species can be altered by dairy products or dairy-derived PL. This finding was consistent with the results of rodent studies. Effects on total PL may be limited by increased fecal excretion. To date, associations with cardiometabolic outcomes are weak and poorly supported by mechanistic studies.
      Associations of PC and LPC species with metabolic dysfunctions have been reported in several studies (
      • Hsu F.F.
      • Bohrer A.
      • Wohltmann M.
      • Ramanadham S.
      • Ma Z.
      • Yarasheski K.
      • Turk J.
      Electrospray ionization mass spectrometric analyses of changes in tissue phospholipid molecular species during the evolution of hyperlipidemia and hyperglycemia in Zucker diabetic fatty rats.
      ;
      • Szymańska E.
      • Bouwman J.
      • Strassburg K.
      • Vervoort J.
      • Kangas A.J.
      • Soininen P.
      • Ala-Korpela M.
      • Westerhuis J.
      • van Duynhoven J.P.
      • Mela D.J.
      • Macdonald I.A.
      • Vreeken R.J.
      • Smilde A.K.
      • Jacobs D.M.
      Gender-dependent associations of metabolite profiles and body fat distribution in a healthy population with central obesity: Towards metabolomics diagnostics.
      ;
      • Ferrannini E.
      • Natali A.
      • Camastra S.
      • Nannipieri M.
      • Mari A.
      • Adam K.P.
      • Milburn M.V.
      • Kastenmuller G.
      • Adamski J.
      • Tuomi T.
      • Lyssenko V.
      • Groop L.
      • Gall W.E.
      Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance.
      ;
      • Cai T.
      • Yang F.
      Phospholipid and phospholipidomics in health and diseases.
      ;
      • Semba R.D.
      • Gonzalez-Freire M.
      • Moaddel R.
      • Sun K.
      • Fabbri E.
      • Zhang P.
      • Carlson O.D.
      • Khadeer M.
      • Chia C.W.
      • Salem Jr., N.
      • Ferrucci L.
      Altered plasma amino acids and lipids associated with abnormal glucose metabolism and insulin resistance in older adults.
      ;
      • Suvitaival T.
      • Bondia-Pons I.
      • Yetukuri L.
      • Poho P.
      • Nolan J.J.
      • Hyotylainen T.
      • Kuusisto J.
      • Oresic M.
      Lipidome as a predictive tool in progression to type 2 diabetes in Finnish men.
      ;
      • Yin X.
      • Willinger C.M.
      • Keefe J.
      • Liu J.
      • Fernandez-Ortiz A.
      • Ibanez B.
      • Penalvo J.
      • Adourian A.
      • Chen G.
      • Corella D.
      • Pamplona R.
      • Portero-Otin M.
      • Jove M.
      • Courchesne P.
      • van Duijn C.M.
      • Fuster V.
      • Ordovas J.M.
      • Demirkan A.
      • Larson M.G.
      • Levy D.
      Lipidomic profiling identifies signatures of metabolic risk.
      ). In a recent cross-sectional study using a targeted metabolomics approach, some PC species (32:0, 32:1, 32:2, 34:1, 34:2, 34:3, 36:2, 36:3, 40:5, 40:6, 42:3, 42:4, and 42:5) were associated with a lower risk of insulin resistance (
      • Semba R.D.
      • Gonzalez-Freire M.
      • Moaddel R.
      • Sun K.
      • Fabbri E.
      • Zhang P.
      • Carlson O.D.
      • Khadeer M.
      • Chia C.W.
      • Salem Jr., N.
      • Ferrucci L.
      Altered plasma amino acids and lipids associated with abnormal glucose metabolism and insulin resistance in older adults.
      ). In addition, LPC 18:0, 18:1, and 17:0 have been identified as negative predictors of type 2 diabetes (
      • Suvitaival T.
      • Bondia-Pons I.
      • Yetukuri L.
      • Poho P.
      • Nolan J.J.
      • Hyotylainen T.
      • Kuusisto J.
      • Oresic M.
      Lipidome as a predictive tool in progression to type 2 diabetes in Finnish men.
      ). In a human study, circulating PC and LPC species rapidly change after even 1 meal that contains a high amount of specific dairy-derived PL, and these extensive alterations remain up to 4 h (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ). The PL content in dairy can possibly compensate for those PC or LPC species that change in the context of metabolic dysfunction. Although mice exhibit significant differences in lipid metabolism versus humans (
      • Bergen W.G.
      • Mersmann H.J.
      Comparative aspects of lipid metabolism: Impact on contemporary research and use of animal models.
      ;
      • Takahashi S.
      • Fukami T.
      • Masuo Y.
      • Brocker C.N.
      • Xie C.
      • Krausz K.W.
      • Wolf C.R.
      • Henderson C.J.
      • Gonzalez F.J.
      Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans.
      ), some animal trials provide data regarding PC and LPC in serum that associate with benefits on insulin sensitivity (
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ) or liver associated with reduced weight gain (
      • Milard M.
      • Laugerette F.
      • Durand A.
      • Buisson C.
      • Meugnier E.
      • Loizon E.
      • Louche-Pelissier C.
      • Sauvinet V.
      • Garnier L.
      • Viel S.
      • Bertrand K.
      • Joffre F.
      • Cheillan D.
      • Humbert L.
      • Rainteau D.
      • Plaisancie P.
      • Bindels L.B.
      • Neyrinck A.M.
      • Delzenne N.M.
      • Michalski M.C.
      Milk polar lipids in a high-fat diet can prevent body weight gain: Modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids.
      ). The circulating PC species including 32:0, 32:1, 32:2, 34:1, 34:3, and 36:3 were considerably elevated after a course of dairy intervention in rodents (
      • Kamili A.
      • Wat E.
      • Chung R.W.
      • Tandy S.
      • Weir J.M.
      • Meikle P.J.
      • Cohn J.S.
      Hepatic accumulation of intestinal cholesterol is decreased and fecal cholesterol excretion is increased in mice fed a high-fat diet supplemented with milk phospholipids.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ). Furthermore, LPC species including 18:0, 18:1, and 17:0 also tended to increase (
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ). Other studies found that milk consumption was associated with lower adiposity, increased insulin sensitivity, and improved glucose homeostasis among diabetic and prediabetic rats (
      • Matsumoto M.
      • Inoue R.
      • Tsuruta T.
      • Hara H.
      • Yajima T.
      Long-term oral administration of cows’ milk improves insulin sensitivity in rats fed a high-sucrose diet.
      ;
      • Yoshimura E.H.
      • Santos N.W.
      • Machado E.
      • Agustinho B.C.
      • Pereira L.M.
      • de Aguiar S.C.
      • Sa-Nakanishi A.B.
      • Mareze-da-Costa C.E.
      • Zeoula L.M.
      Functionality of cow milk naturally enriched with polyunsaturated fatty acids and polyphenols in diets for diabetic rats.
      ). In addition to milk intake, yogurt consumption enhanced insulin sensitivity in rodents (
      • Johnson M.S.
      • Jumbo-Lucioni P.
      • Watts A.J.
      • Allison D.B.
      • Nagy T.R.
      Effect of dairy supplementation on body composition and insulin resistance in mice.
      ;
      • Qu L.
      • Ren J.
      • Huang L.
      • Pang B.
      • Liu X.
      • Liu X.
      • Li B.
      • Shan Y.
      Antidiabetic effects of lactobacillus casei fermented yogurt through reshaping gut microbiota structure in type 2 diabetic rats.
      ;
      • Lasker S.
      • Rahman M.M.
      • Parvez F.
      • Zamila M.
      • Miah P.
      • Nahar K.
      • Kabir F.
      • Sharmin S.B.
      • Subhan N.
      • Ahsan G.U.
      • Alam M.A.
      High-fat diet-induced metabolic syndrome and oxidative stress in obese rats are ameliorated by yogurt supplementation.
      ). However, these studies did not report PC and LPC, and hence the degree to which long-term dairy food intervention increase food-specific PC and LPC species is only reported by
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      .
      Furthermore, plasma PL species are highly sensitive markers of the fatty acid composition of acute interventions (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ), persisting up to 3 wk (
      • Hlavatý P.
      • Kunešová M.
      • Gojová M.
      • Tvrzická E.
      • Vecka M.
      • Roubal P.
      • Hill M.
      • Hlavatá K.
      • Kalousková P.
      • Hainer V.
      • Žák A.
      • Drbohlav J.
      Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls.
      ). However, the circulating PC and LPC species that were increased following the intervention were not all specifically dairy-derived (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ). Untargeted metabolomic analyses also indicated a great many more PL species were altered that might not be directly attributable to intake of dairy products or milk-PL (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Zheng H.
      • Lorenzen J.K.
      • Astrup A.
      • Larsen L.H.
      • Yde C.C.
      • Clausen M.R.
      • Bertram H.C.
      Metabolic effects of a 24-week energy-restricted intervention combined with low or high dairy intake in overweight women: An NMR-based metabolomics investigation.
      ). The capacity of meal-derived lipids to alter plasma PL pools is determined by absorption and subsequent metabolic processes, as well as the quantity of lipid in the meal and the size of the plasma PL pools (
      • Lambert J.E.
      • Parks E.J.
      Postprandial metabolism of meal triglyceride in humans.
      ). Extensive processing or differences in the food matrix likely affect the PL content of dairy foods and their absorption; thus, it is tempting to speculate that individual dairy products have a specific effect on the serum concentration of PL species. Therefore, short- and long-term human studies are needed to elucidate how PL and its species are regulated in response to different types of dairy products. In addition, animal studies are also required to determine the mechanism and improve our understanding of how dairy foods change PL species, particularly those not attributable to dairy sources (
      • Meikle P.J.
      • Barlow C.K.
      • Mellett N.A.
      • Mundra P.A.
      • Bonham M.P.
      • Larsen A.
      • Cameron-Smith D.
      • Sinclair A.
      • Nestel P.J.
      • Wong G.
      Postprandial plasma phospholipids in men are influenced by the source of dietary fat.
      ;
      • Hanning A.R.
      • Wang X.
      • Hashemi Z.
      • Wan S.
      • England A.
      • Jacobs R.L.
      • Chan C.B.
      Both low- and regular-fat cheeses mediate improved insulin sensitivity and modulate serum phospholipid profiles in insulin-resistant rats.
      ).
      Human trials of healthy participants using dairy enriched in PL (
      • Keller S.
      • Malarski A.
      • Reuther C.
      • Kertscher R.
      • Kiehntopf M.
      • Jahreis G.
      Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers.
      ,
      • Keller S.
      • Le H.Y.
      • Rodiger C.
      • Hipler U.C.
      • Kertscher R.
      • Malarski A.
      • Hunstock L.M.
      • Kiehntopf M.
      • Kaatz M.
      • Norgauer J.
      • Jahreis G.
      Supplementation of a dairy drink enriched with milk phospholipids in patients with atopic dermatitis—A double-blind, placebo-controlled, randomized, cross-over study.
      ) found alterations in circulating cholesterol, but because total circulating PL and PC were not changed, the mechanism is unclear. Possibly, measuring incorporation of dairy-derived PL into membranes could shed additional information. Studies of people with cardiovascular disease risk yielded variable cardiometabolic outcomes, but these could not be attributed to dairy interventions in most cases (
      • Weiland A.
      • Bub A.
      • Barth S.W.
      • Schrezenmeir J.
      • Pfeuffer M.
      Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men—Two double-blind, randomised, controlled, clinical trials.
      ). In contrast, in trials where the intervention increased dairy-derived fatty acids in the PL fraction, no metabolic improvements including insulin sensitivity or plasma lipids were observed (30) and 1 study did not report metabolic outcomes (
      • Markey O.
      • Vasilopoulou D.
      • Kliem K.E.
      • Koulman A.
      • Fagan C.C.
      • Summerhill K.
      • Wang L.Y.
      • Grandison A.S.
      • Humphries D.J.
      • Todd S.
      • Jackson K.G.
      • Givens D.I.
      • Lovegrove J.A.
      Plasma phospholipid fatty acid profile confirms compliance to a novel saturated fat-reduced, monounsaturated fat-enriched dairy product intervention in adults at moderate cardiovascular risk: a randomized controlled trial.
      ). A current meta-analysis of 30 human RCT of dairy interventions showed a beneficial effect on homeostatic model assessment for insulin resistance (
      • Sochol K.M.
      • Johns T.S.
      • Buttar R.S.
      • Randhawa L.
      • Sanchez E.
      • Gal M.
      • Lestrade K.
      • Merzkani M.
      • Abramowitz M.K.
      • Mossavar-Rahmani Y.
      • Melamed M.L.
      The effects of dairy intake on insulin resistance: A systematic review and meta-analysis of randomized clinical trials.
      ); however, the effect of individual dairy foods was not presented nor were PL measured. Furthermore, based on findings from clinical studies (
      • Pietiläinen K.H.
      • Sysi-Aho M.
      • Rissanen A.
      • Seppänen-Laakso T.
      • Yki-Järvinen H.
      • Kaprio J.
      • Orešič M.
      Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects—A monozygotic twin study.
      ;
      • Wahl S.
      • Yu Z.
      • Kleber M.
      • Singmann P.
      • Holzapfel C.
      • He Y.
      • Mittelstrass K.
      • Polonikov A.
      • Prehn C.
      • Romisch-Margl W.
      • Adamski J.
      • Suhre K.
      • Grallert H.
      • Illig T.
      • Wang-Sattler R.
      • Reinehr T.
      Childhood obesity is associated with changes in the serum metabolite profile.
      ;
      • Martínez-Ramírez M.
      • Madero M.
      • Vargas-Alarcon G.
      • Vargas-Barron J.
      • Fragoso J.M.
      • Rodriguez-Perez J.M.
      • Martinez-Sanchez C.
      • Gonzalez-Pacheco H.
      • Bautista-Perez R.
      • Carreon-Torres E.
      • Perez-Mendez O.
      HDL-sphingomyelin reduction after weight loss by an energy-restricted diet is associated with the improvement of lipid profile, blood pressure, and decrease of insulin resistance in overweight/obese patients.
      ), an RCT in humans with impaired PL subclasses is required to measure the efficacy of dairy PL from different dairy foods on PL subclasses and species and any associated benefits on glucose and lipid metabolism or body composition.
      In the current scoping review, we focus on the most highly consumed dairy products, milk, yogurt, and cheese, as the greatest source of dairy-derived PL in the diet. For example, in a nationally representative sample of adult Canadians, these 3 products plus frozen dairy products contribute >95% of total dairy intake (
      • Auclair O.
      • Han Y.
      • Burgos S.A.
      Consumption of milk and alternatives and their contribution to nutrient intakes among Canadian adults: Evidence from the 2015 Canadian Community Health Survey—Nutrition.
      ). There are also various milk-based products with high content of PL that are consumed in lower amounts, such as buttermilk, cream, and butter that were excluded from this review. In this regard, an 8-wk single-blind, parallel-group RCT with 1 dL per day of whipping cream (139 to 190 mg of PL per 100 g) did not affect plasma total PL and PL species. However, increases in LDL cholesterol, non-high-density lipoprotein cholesterol, ApoB, and total cholesterol were observed compared with a control group consuming milk protein isolate (
      • Rosqvist F.
      • Smedman A.
      • Lindmark-Mansson H.
      • Paulsson M.
      • Petrus P.
      • Straniero S.
      • Rudling M.
      • Dahlman I.
      • Riserus U.
      Potential role of milk fat globule membrane in modulating plasma lipoproteins, gene expression, and cholesterol metabolism in humans: A randomized study.
      ), which might be attributable, at least in part, to the saturated fat content. Another double-blinded randomized crossover placebo-controlled study indicated that 4 wk of buttermilk (93.7 mg of PL per day) consumption significantly reduced serum total cholesterol and triglyceride concentrations compared with the placebo (17.3 mg of PL) group, but effects on circulating PL were not reported (
      • Conway V.
      • Couture P.
      • Richard C.
      • Gauthier S.F.
      • Pouliot Y.
      • Lamarche B.
      Impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol homeostasis in men and women.
      ). Results of these 2 studies do not alter our conclusion that consumption of dairy PL does not alter total circulating PL. However, further studies comparing individual dairy foods' effects, including those with naturally high PL concentrations, on specific species of PL and potential biological outcomes are warranted.
      This review has identified other limitations and gaps in the current literature. Heterogeneity in designs, methodology, and reporting in the included studies, makes conclusions challenging. Lipid metabolism differs between species limiting the transposition of findings from rodents to humans; however, some general similarities between humans and rodents support using rodents as a model for many aspects of human lipid metabolism (
      • Gordon S.M.
      • Li H.
      • Zhu X.
      • Shah A.S.
      • Lu L.J.
      • Davidson W.S.
      A comparison of the mouse and human lipoproteome: Suitability of the mouse model for studies of human lipoproteins.
      ,
      • Kaabia Z.
      • Poirier J.
      • Moughaizel M.
      • Aguesse A.
      • Billon-Crossouard S.
      • Fall F.
      • Durand M.
      • Dagher E.
      • Krempf M.
      • Croyal M.
      Plasma lipidomic analysis reveals strong similarities between lipid fingerprints in human, hamster and mouse compared to other animal species.
      ). Questions requiring further consideration are the extent to which PC or LPC species are raised after intervention by dairy products and the involvement of metabolic pathways that regulate the balance of PL species. In the current scoping review, we included studies that intervened with milk, yogurt, and cheese, all classified according to dairy products on MyPlate, the USDA dietary guidelines. However, other milk-based foods high in fat but still rich in PL, such as cream and buttermilk, were excluded. It is a possible limitation of the current work, and the effect of PL concentration might also be interesting. Another limitation was the potential confounding effect of participants' habitual dietary intake before and during the intervention in human trials. Dairy foods may be consumed in processed or other foods, leading to underestimating the actual intake of dairy products, especially in the control groups. Because PL or its subclasses was not the primary outcome in most studies, results should be interpreted with caution because nonsignificant changes might result from lack of power rather than actual effect. The physiological basis for benefits of dairy PC and LPC on metabolism remains unclear, with evidence to the contrary also reported (
      • Liu P.
      • Zhu W.
      • Chen C.
      • Yan B.
      • Zhu L.
      • Chen X.
      • Peng C.
      The mechanisms of lysophosphatidylcholine in the development of diseases.
      ). Future research is needed to fill up the gaps and limitations in order to explore the effect of dairy foods on PL metabolism. Nonetheless, the current scoping review covered research using a variety of methodologies, allowing us to compile data from human and animal studies evaluating dairy-derived PL under various settings and, as a result, identify features that could be improved in future studies. As a strength of this study, the application of multiple databases provides a broader range of published papers and contribution of 2 researchers to conduct the literature search and study assessments for quality control.

      CONCLUSIONS

      Experimental and clinical studies provide evidence that total circulating PL is tightly regulated, even in interventions with a high milk-PL dosage. Data regarding the impact of dairy on total PC and LPC remain inconclusive. However, their species in the blood or liver have been repeatedly altered in response to dairy products without significant changes in total circulating PC. Our scoping review identified the need for additional human studies with a large number of participants and with a specific focus on individual dairy products, detailed dietary data, and strict intake control to provide stronger evidence and overcome the limitations previously discussed. Additional animal trials are warranted to describe better the PL-related metabolic pathways linked to the individual dairy products.

      ACKNOWLEDGMENTS

      Author contributions are as follows: E.Y. and C.B.C. conceptualized, designed the study; E.Y. and S.M. conducted the search, selection, and evaluation of studies; E.Y. prepared the first draft of the manuscript, which was subsequently finalized in close collaboration with C.B.C. and S.M.; C.B.C. supervised the project and revised and approved the final version of the manuscript; and all authors read and approved the final manuscript. E.Y. is a recipient of a 2020 ADI/HRD Graduate Studentship funded by the Alberta Diabetes Institute (Edmonton, Canada) and International Helmholtz Research School for Diabetes (Munich, Germany). The Canadian Bureau for International Education (Ottawa, Canada) supports S.M. Data sharing is not applicable to this article as no new data were created or analyzed in this study. This research received no external funding. No live human or animal subjects were used in this review, and ethical approval for the study was thus deemed unnecessary. The authors have not stated any conflicts of interest.