This project previously identified the membrane scavenger receptor CD36 as a facilitator of cellular uptake of long chain fatty acid (FA) and showed that its deletion in mice markedly reduces FA uptake by heart, skeletal muscle and adipose tissue. The deletion also reduces gut chylomicron secretion and delays clearance of postprandial lipids. This renewal submission is focused on CD36-dependent FA signaling. CD36 can transduce intracellular signals through its interaction with tyrosine kinases and our recent findings support importance of this signaling in determining the metabolic fate of the FA. FA-induced CD36 signaling triggers conversion of polyunsaturated FA into the bioactive eicosanoids, mediates neurotransmitter release for gustatory fat perception, directs absorbed FA to chylomicron formation and triggers release by enteroendocrine cells of cholecystokinin and secretin, peptides with important roles in fat absorption and satiety. Our preliminary data also show that in myocytes, FA uptake enhances FA oxidation via CD36 signaling to activate the LKB1-AMPK pathway. Importance of CD36 to human FA metabolism was demonstrated by several groups including ours and genetic variants in CD36 were shown to associate with risk of the metabolic syndrome. Our recent data on the relationships between tissue expression profiles of CD36 transcripts and insulin sensitivity of obese subjects strongly support a key role for adipocyte CD36, which was a significant predictor of insulin sensitivity systemically and in liver and muscle.
In aim 1, we will determine the metabolic and disease significance of CD36-mediated FA signaling using in vitro cell systems and mice models.
In aim 2, we propose based on our recent identification of the CD36 amino acid residue required for FA uptake and signaling to examine the structural properties of the FA binding pocket and the influence of FA binding on CD36 membrane configuration. The CD36-protein interactions important for signal transduction will also be examined.
In aim 3, to gain insight into tissue specific regulation of CD36 level which determines FA homeostasis across tissues we will explore the factors that regulate alternate promoter usage of the human CD36 gene and the stability of alternate transcripts. The studies proposed should provide information on the importance of FA signaling in the regulation of FA utilization and metabolic health. The insight generated into CD36 structure and the regulation of tissue CD36 expression could help design strategies to target the protein more specifically and in a tissue specific manner.

Public Health Relevance

CD36 is a key metabolic protein in humans that functions in cellular fatty acid (FA) uptake and intracellular signaling and has been linked to the risk of the metabolic syndrome. Our recent data support importance of CD36 signaling in FA homeostasis and of adipocyte CD36 in systemic and tissue (liver, muscle) insulin sensitivity. The work proposed will provide insight into CD36 function, its structure in the membrane and the tissue specific regulation of its expression. It could help design more specific strategies to target CD36 in a tissue specific manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK033301-28
Application #
8697642
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Pawlyk, Aaron
Project Start
1983-12-01
Project End
2018-03-31
Budget Start
2014-04-08
Budget End
2015-03-31
Support Year
28
Fiscal Year
2014
Total Cost
$339,034
Indirect Cost
$116,534
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Clugston, Robin D; Yuen, Jason J; Hu, Yunying et al. (2014) CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis. J Lipid Res 55:239-46
Ozdener, Mehmet Hakan; Subramaniam, Selvakumar; Sundaresan, Sinju et al. (2014) CD36- and GPR120-mediated Ca²? signaling in human taste bud cells mediates differential responses to fatty acids and is altered in obese mice. Gastroenterology 146:995-1005
Pietka, Terri A; Schappe, Timothy; Conte, Caterina et al. (2014) Adipose and muscle tissue profile of CD36 transcripts in obese subjects highlights the role of CD36 in fatty acid homeostasis and insulin resistance. Diabetes Care 37:1990-7
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Sundaresan, Sinju; Shahid, Rafiq; Riehl, Terrence E et al. (2013) CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin. FASEB J 27:1191-202
Iso, Tatsuya; Maeda, Kazuhisa; Hanaoka, Hirofumi et al. (2013) Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol 33:2549-57
Abumrad, Nada A; Piomelli, Daniele; Yurko-Mauro, Karin et al. (2012) Moving beyond "good fat, bad fat": the complex roles of dietary lipids in cellular function and health: session abstracts. Adv Nutr 3:60-8
Pepino, Marta Yanina; Love-Gregory, Latisha; Klein, Samuel et al. (2012) The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects. J Lipid Res 53:561-6

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