Functional Foods for Health Promotion : Moving Beyond “ Good Fat , Bad Fat ” Moving Beyond “ Good Fat , Bad Fat ” : The Complex Roles of Dietary Lipids in Cellular Function and Health 1 , 2

The International Life Science Institute North America and the American Society for Nutrition annual Functional Foods for Health Symposium was held 9 April 2011. Evidence that foods and their components offer health benefits beyond basic nutrition continues to captivate the interest of the scientific community, government agencies, and the general public. This paper is comprised of extended abstracts from the session and addresses issues related to emerging lipid nutrition science, including active roles of lipids in modulating physiological pathways. Identified pathways underlie the development of obesity, cognitive development, and inflammation, the latter of which is thought to relate to multiple disease processes. These data point to a new way of thinking about the role of lipids in health and disease. Adv. Nutr. 3: 60–68, 2012. Session Abstracts A similar pathway may mediate cd36 involvement in fat taste perception and inflammation Nada A. Abumrad The membrane scavenger receptor FAT/CD36 has broad specificity and can recognize a number of ligands. It plays an important role in long chain FA metabolism in both rodents and humans (1). In CD36-deficient mice and rats, studies of FA biodistribution in vivo documented that CD36 contributes a major part of FA uptake into the heart, skeletal muscle, and adipose tissues. CD36 has been implicated in mediating fat taste perception. Localized on the apical face of taste bud cells, the protein, after interaction with long chain FA, transduces signals that increase intracellular calcium and associate with neurotransmitter release (2). CD36 also functions in the uptake of oxidized LDL by macrophages, promoting their conversion into foam cells, and its deletion has a protective antiatherosclerotic effect (3). As a result, altered CD36 function has been proposed to contribute to multiple abnormalities of lipid metabolism. Variations in the CD36 gene are common in humans and SNPs (frequency between 10 and 40%) associate with blood 1 Published as a supplement to Advances in Nutrition. Presented as part of the symposium entitled “Functional Foods for Health Promotion: Moving beyond “Good Fat, Bad Fat” given at the Experimental Biology 2011 meeting, April 9, 2011, in Washington, DC. The symposium was sponsored by the International Life Science Institute, North American Branch. The symposium was chaired by John Milner and Brent Flickinger. Guest Editor for this symposium publication was John Suttie. Guest Editor disclosure: There were no conflicts to disclose. 2 Supported by NIH grants P01 HL057278, R01 DK33301, DK56351, GM069338 (Lipid Maps), GM76217, CA137812. DE019938, NS067686, and GM038765. The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Dental and Craniofacial Research, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, or the NIH. 3 Author disclosures: C.S. is inventor on patents assigned to BWH-Partners HealthCare on the composition, uses, and clinical development of antiinflammatory and proresolving mediators and related compounds. These are licensed for clinical development: lipoxins to Bayer HealthCare, resolvins, and related materials to Resolvyx Pharmaceuticals. C.S. retains founder stock in Resolvyx. N.A., D.P., K.Y-M., A.M., and M.T.C., no conflicts of interest. All speakers except K.Y-M. received travel funding and a modest honorarium for participation in the meeting and manuscript preparation. * To whom correspondence should be addressed. E-mail: Marie E. Latulippe, mlatulippe@ilsi. org. 9 Abbreviations used: AA, arachidonic acid; AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale; ADCS, Alzheimer’s Disease Cooperative Study group; ARCD, age-related cognitive decline; Cer, ceramide; cPLA2, cytoplasmic phospholipase A2; DG, diglyceride; ER, endoplasmic reticulum; FA, fatty acid; GPCR, g-protein coupled receptor; MCI, mild cognitive impairment; MIDAS, Memory Improvement with DHA Study; miRNA, microRNA; MMSE, Mini-Mental State Exam; OEA, oleoylethanolamide; PAF, platelet-activating factor; PAL, Paired Associate Learning; RvD1, resolvin; SNP, single nucleotide polymorphism; SPM, specialized proresolving mediator. 60 ã2012 American Society for Nutrition. Adv. Nutr. 3: 60–68, 2012; doi:10.3945/an.111.000802. D ow naded rom http/academ ic.p.com /advances/arstract/3/1/60/4557088 by gest on 12 M arch 2019 lipid levels, positively with VLDL and negatively with HDL (4). A common haplotype in the CD36 gene associates with blood FFA (5) and CD36 SNPs influence individual variability in response of blood lipids to (n-3) FA supplementation (6). CD36 SNPs associate with risk of coronary heart disease in diabetic individuals with risk of metabolic syndrome and stroke (5,4,7). In addition to its functions in substrate uptake, CD36 interacts with src kinases and participates in intracellular signal transduction (3, 8). This signaling function was shown to be important for fat taste perception in taste bud cells. In studies with mice, it was shown that CD36 deletion impairs spontaneous fat preference and the mechanism involved cellular calcium dynamics with the subsequent release of neurotransmitters (9). CD36 signaling is also postulated to mediate the role of the protein in inflammation. It has been well established that in several cell types, including macrophages’ excess supply of the CD36 ligands, FA and oxidized LDL can promote oxidative and ER stress and signaling to stress kinases. As a result, CD36 is implicated in the inflammation associated with diabetes and atherosclerosis (3). Our recent work documents that one important mechanism for CD36’s role in inflammation may involve a pathway similar to that functioning in fat taste perception. We show that CD36 is required for membrane calcium influx in response to ER stress and that one consequence of this role is the regulated release of AA from cellular membranes by cPLA2 (8). Release of AA is the trigger for the formation of eicosanoids, bioactive molecules with pleiotropic effects in acute inflammation. Eicosanoids derived from AA, an (n-6) PUFA, have proinflammatory functions in contrast to (n-3) PUFA-derived eicosanoids, which have antiinflammatory properties (10). Our findings would explain at least some of the proinflammatory effects of CD36, especially those related to the acute inflammatory response. This novel function of CD36 integrates regulation of FA utilization, cellular calcium homeostasis, and inflammation. Further studies of how this is accomplished are important to our understanding of the etiology of diet-induced inflammatory processes and their contribution to disease. Various factors (e.g. purinergic receptor agonists, ATP and UTP) or events (e.g. cellular stress) release calcium from the ER. Inhibition of the ER calcium pump SERCA2 is one commonmethod to deplete ER calcium by preventing its reuptake (Fig. 1). The increase in cytosolic calcium drives CD36 to the plasma membrane (possibly by inhibiting its internalization). CD36 at the membrane regulates activation of store-operated calcium channels (channels responsive to ER calcium depletion) via its interaction with the Src family kinase Fyn. The sustained rise in intracellular calcium translocates cPLA2 to nuclear and ER membranes, where it acts to release AA from the sn-2 position of phospholipids. The enzyme is also activated via CD36-dependent phosphorylation by the MAP kinase ERK1/2. The AA produced by cPLA2 is converted by cyclooxygenases into eicosanoids, which have pleiotropic effects in inflammation. One of the major products formed from AA by the cyclooxygenase pathway is PGE2. Literature Cited 1. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends in endocrinology and metabolism. Trends Endocrinol Metab. 2009;20:72–7. 2. El-Yassimi A, Hichami A, Besnard P, Khan NA. Linoleic acid induces calcium signaling, Src kinase phosphorylation, and neurotransmitter release in mouse CD36-positive gustatory cells. J Biol Chem. 2008;