Research supported by this grant has resulted in the identification of the membrane protein CD36 as an important facilitator of long-chain fatty acid uptake by several key metabolic tissues such as muscle and heart. In the last funding period, we have established the important physiological role of CD36 and documented how alterations in its expression level lead to abnormalities in the metabolism of both fatty acids and glucose. It was also shown that both CD36 deficiency and overexpression can modulate insulin sensitivity and the metabolic response to the diet. In the next funding period, our first objective will be to use the various animal models now available with genetically altered CD36 levels to gain a better understanding of the interaction between the metabolisms of fatty acids and glucose and on how this impacts susceptibility to insulin resistance. We will explore the molecular mechanisms that underlie some of these interactions. Our second objective is to examine the role of CD36 in the cross talk between adipose and muscle tissues by asking whether CD36 regulation plays a primary role in mediating the peripheral effects of leptin and ACRP30. These substances are released by adipose tissue to act on fatty acid oxidation by muscle and we postulate that they acutely and chronically regulate muscle CD36 levels. Our final objective is to determine the major factors that regulate fatty acid transport and CD36 membrane localization/function in muscle cells. The work proposed has physiological and potentially clinical significance. In humans, CD36 deficiency is as high as 18% in some subpopulations and it may be an important factor in the metabolic adaptation to diet and in susceptibility to some forms of diet-induced pathology. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033301-20
Application #
6953086
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (02))
Program Officer
Haft, Carol R
Project Start
1983-12-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
20
Fiscal Year
2005
Total Cost
$323,595
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Samovski, Dmitri; Dhule, Pallavi; Pietka, Terri et al. (2018) Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling. Diabetes 67:1272-1284
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
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
Shibao, Cyndya A; Celedonio, Jorge E; Ramirez, Claudia E et al. (2016) A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition. J Clin Endocrinol Metab 101:2751-8
Hu, Xiaoqian; Cifarelli, Vincenza; Sun, Shishuo et al. (2016) Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment. J Lipid Res 57:663-73

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