CD36 is a multifunctional membrane protein we identified in 1993 as a facilitator of long-chain fatty acid (FA) uptake. This role of CD36 is now supported by a wealth of in vivo evidence obtained by us and by others. This grant was initially submitted to examine the role of CD36 in lipid absorption in the small intestine, based on its high expression and its distribution along the gastro-colonic axis, which are consistent with a role in lipid transport.
Our aims were to define any defects in absorption and chylomicron production in CD36 null mice and to examine susceptibility to high fat diet-induced obesity. Other studies proposed to examine the role of CD36 in directing the FA to chylomicron production and possible interactions between CD36 and other proteins implicated in FA binding and utilization in the intestine. During the funding of this grant we demonstrated a defect in lipid processing by the intestine of the CD36 null mouse. Secretion of lipid in the ymph was also found to be 50% depressed with a defect in chylomicron production and a shift to more VLDL reduction. Our recent work with primary enterocytes indicates that the defect in secretion is consequent to mpairments in FA and cholesterol uptake in the proximal intestine. Finally, we have documented severely mpaired clearance of postprandial lipoproteins in the CD36 null mouse which interferes with attempts to measure the metabolic impact of CD36 deficiency at the level of the intestine. Based on the above the current application proposes to examine the hypothesis that the presence of CD36 at the enterocyte apical membrane targets the fatty acid to the monoacylglycerol pathway of triglyceride formation that feeds chylomicron production. More specifically we will examine the role of CD36 in transfer of triglycerides to the endoplasmic reticulum (ER) and from the ER to the Golgi. Our second goal is to explore whether targeting CD36 in the intestine, alone or in combination with targeting L-FABP, can lower postprandial blood triglycerides for improving outcome in obesity or diabetes. We will test this by generating a mouse with intestine-specific deficiency of CD36 on the WT and L-FABP null backgrounds. Third our recent data indicate a role of CD36 in the release of intestinal incretins and we will examine the implications of this role with respect to fat intake and insulin secretion. Fourth we propose to examine the metabolic impact of CD36 deficiency in humans with respect to lipid absorption, clearance of postprandial lipoproteins and incretin release. CD36 deficiency in humans has been reported to be associated with abnormalities of blood lipids in both the postprandial and fasted states. The studies will expand our knowledge of the molecular mechanisms underlying chylomicron formation and incretin release. They will provide insight into the contribution of dysfunctions in intestinal CD36 to the etiology of hypertriglyceredemia in humans.
|Perry, Justin S A; Russler-Germain, Emilie V; Zhou, You W et al. (2018) Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance. Immunity 48:1271|
|Samovski, Dmitri; Dhule, Pallavi; Pietka, Terri et al. (2018) Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling. Diabetes 67:1272-1284|
|Ladanyi, Andras; Mukherjee, Abir; Kenny, Hilary A et al. (2018) Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37:2285-2301|
|Shibao, Cyndya A; Celedonio, Jorge E; Tamboli, Robyn et al. (2018) CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels. J Clin Endocrinol Metab 103:1856-1866|
|Cifarelli, Vincenza; Abumrad, Nada A (2018) Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis. Compr Physiol 8:493-507|
|Son, Ni-Huiping; Basu, Debapriya; Samovski, Dmitri et al. (2018) Endothelial cell CD36 optimizes tissue fatty acid uptake. J Clin Invest 128:4329-4342|
|Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315|
|Tomassini Barbarossa, Iole; Ozdener, M Hakan; Melania et al. (2017) Variant in a common odorant-binding protein gene is associated with bitter sensitivity in people. Behav Brain Res 329:200-204|
|Cifarelli, Vincenza; Ivanov, Stoyan; Xie, Yan et al. (2017) CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice. Cell Mol Gastroenterol Hepatol 3:82-98|
|Xie, Yan; Cifarelli, Vincenza; Pietka, Terri et al. (2017) Cd36 knockout mice are protected against lithogenic diet-induced gallstones. J Lipid Res 58:1692-1701|
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