The scavenger receptor CD36 has lipid and non-lipid ligands and versatile functions in metabolism and immunity. An important function of CD36 is its ability to transduce intracellular signals triggered by its ligands. CD36 signaling contributes to the regulation of several aspects of fatty acid (FA) utilization such as fat taste perception, chylomicron production, enteroendocrine secretion, FA oxidation etc. We recently showed that CD36 interacts with the AMPK and insulin signaling pathways and we propose that this mediates an important part of its actions on nutrient utilization. We document presence of CD36 in a molecular complex with insulin receptor beta (IR?) and CD36-mediated recruitment to IR? of Fyn and the catalytic p85 subunit of PI3-kinase. We also find that palmitic acid binding to CD36 interferes with Fyn and p85 recruitment and blunts Akt phosphorylation. In this project, which involves a multidisciplinary collaboration between basic and clinical scientists, we will test the novel hypothesis that the membrane protein CD36 via its interaction with the PI3K pathway influences endothelial cell function, insulin?s action on microvasculature recruitment and consequently nutrient flux and the effect of high fat feeding to cause endothelial dysfunction. Our preliminary data document diminished vascular compliance in CD36-/- mice and more importantly in African Americans carrying coding SNP rs3211938 that reduces CD36 level by 50%. We will examine the functional implications of CD36 signaling in endothelial cells and the consequences of endothelial cell CD36 deletion in mice on vascular function and insulin regulation of tissue perfusion and energetics. We will determine in these mice the effect of high fat feeding to induce endothelial dysfunction and whether this is reversed by treatment with phosphodiesterase 5 (PDE5) inhibition which blocks cGMP degradation. In a parallel approach we will examine influence of partial CD36 deficiency in African American carriers of rs3211938 on endothelial dysfunction, microvascular recruitment by insulin and the efficacy of PDE5 inhibition treatment. Obesity and endothelial dysfunction are highly prevalent especially in African Americans and associate with negative cardiovascular and metabolic outcomes. The proposed work will provide fundamental information that is currently unavailable and that could influence treatment of endothelial dysfunction and insulin resistance in humans.

Public Health Relevance

This project will test a novel hypothesis that might provide insight into an unexplored mechanism of diet- induced endothelial dysfunction. Endothelial dysfunction characterized by vascular stiffening occurs in 12% of adults under 50 years of age and precedes onset of hypertension, insulin resistance and diabetes. It is a major cause of dementia, stroke, renal failure, myocardial infarction and cardiovascular disease. The information generated by the work proposed might result in new biomarkers for susceptibility to endothelial dysfunction and guide approaches for prevention or therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK111175-04
Application #
9741119
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2016-07-15
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
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
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
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
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

Showing the most recent 10 out of 11 publications