CD36, or scavenger receptor B2, is highly conserved through evolution and has metabolic and immune functions. Our findings together suggest that CD36 has five major functions in the gut: 1) FA uptake by the proximal intestine, 2) initiation of chylomicron synthesis and chylomicron input into the lymph, 3) mounting of a full immune response to enteric pathogens, 4) facilitating neutrophil clearance and 5) extracellular matrix (ECM) remodeling and tissue repair . Based on our recent findings we propose that low or dysfunctional gut CD36 can be a susceptibility gene for dietary fat induced gut inflammation. Our hypothesis is that abnormal ECM remodeling will induce gut inflammation and together with impaired immune cell function will lead to progression of gut inflammation to the systemic level involving multiple organs with development of whole body insulin resistance. Indeed, subclinical inflammation appears present in obese subjects carrying the minor allele of a coding SNP that reduces CD36 level by 50%. The studies we propose in aim 1 will examine CD36?s role in dietary fat induced alterations of ECM remodeling and immunity in the gut and will yield information relevant to etiology of major complications of obesity. We will also conduct immune cell profiling of subjects with CD36 deficiency. Another way by which the gut influences systemic homeostasis is through secretions of the preabsorptive phase. This phase in people is important for optimal nutrient processing and energy metabolism. However, little is known about its regulation and why it is blunted in type-2 diabetes. Our preliminary data indicate blunting of preabsorptive secretions in individuals with partial CD36 deficiency. We propose in aim 2 to study the components of the preabsorptive phase in CD36-/- mice and to determine if it is mediated by CD36 expression on vagal neurons using a new mouse generated by deletion of CD36 in preganglionic parasympathetic neurons using the Phox2b-Cre.
In aim 3 we will study the role of CD36 in the stomach. Expression of CD36 in the stomach is among the highest in the mouse (data not shown) and although it was demonstrated in 2001 any role of CD36 in the stomach has not been examined. Our preliminary data indicate CD36 is highly expressed on endothelial cells (EC) and parietal cells (PC) in the stomach and CD36 deletion alters PC morphology and function. We will examine how CD36 deletion in EC or PC impacts PC metabolism and function and the impact on ECM remodeling and response to injury from high fat diet, high tamoxifen treatment or H pylori infection. Overall the studies in aims 1-3 are will increase our understanding of gut homeostatic functions, how they are altered by excess dietary fat and the associated systemic implications. The information obtained could help design novel therapeutic approaches to alleviate gut inflammation and its systemic impact.
CD36 has both metabolic and immune functions. Genetic associations studies showed that variations that alter CD36 level associate with abnormal blood lipids and with risk of metabolic syndrome (MetS), findings later confirmed in genome wide association studies. MetS with a current US prevalence of 33% increases risk of diabetes and cardiovascular disease. We recently showed that CD36 is important for maintaining the epithelial barrier in the small intestine and its deletion resulted in leaky barrier and inflammation. This project examines the mechanisms that underlie CD36?s influence on intestine and stomach health. It also explores CD36?s role in the tissue response to injury induced by excess intake of dietary fat and the local and systemic implications involved.
|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|
|Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142|
|Abumrad, Nada A (2017) The Liver as a Hub in Thermogenesis. Cell Metab 26:454-455|
|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|
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