The PI's laboratory focuses on the pathways leading to lipid uptake by tissues. We have produced new information on the physiologic roles of lipoprotein lipase (LpL) in regulation of plasma lipids, uptake of fatty acids into tissues and internalization of core lipids. In addition, we have shown that augmenting fatty acid esterificatio into cellular triglyceride improves skeletal muscle insulin resistance and cardiac function in models of lipid overload, i.e. lipotoxicity. More recently our laboratory has shown that cluster of differentiation (CD) 36, which regulates plasma free fatty acid (FFA) levels and affects peripheral tissue accumulation of fatty acids, mediates heart accumulation of VLDL-, but not chylomicron-, derived fatty acids. This established in vivo that there are at least two pathways of FFA uptake into tissues. In this renewal we propose to study the pathways required for uptake of both FFAs and lipoprotein-derived fatty acids by altering expression of both LpL and CD36. We have created floxed CD36 mice and present preliminary data showing that loss of CD36 expression in endothelial cells alters parenchymal tissue expression of genes related to fatty acid and glucose metabolism, plasma FFA levels, and lipid droplet formation. Characterization of the role of endothelial CD36 will illustrate how FFAs cross the endothelial barrier, a step required for their uptake into adipocytes and myocytes. In addition, building on data showing that LpL overexpression in skeletal muscle reduces adipose tissue mass, we will dissect the roles of circulating triglyceride-derived fatty acids and FFAs in adipose and muscle lipid metabolism.
In Aim 1 we will determine adipose and skeletal muscle lipid metabolism in endothelial cell specific CD36 deleted mice. Moreover, we will further assess the FFA transport pathways by studies of isolated vessels and endothelial cell monolayers. Finally, we will determine if loss of endothelial cell CD36 protect tissues from excess lipid accumulation leading to toxicity. These studies will provide basic information on how lipids are delivered to tissues fo energy production and storage.
In Aim 2 we propose experiments to determine why parenchymal cell LpL deletion, which affects metabolism in muscle and brown adipose tissue, only affects white adipose tissue when LpL is overexpressed in skeletal muscle. To study this we will assess whether changes in hepatic triglyceride production or diversion of lipids to skeletal muscle, or both, are required for reduced lipid uptake by adipose. These studies will illustrate how the body distributes calories between organs. Our work aims to define the basic processes that underlie the physiologic and pathological storage of lipids in tissues. Such information will suggest novel ways to disrupt the pathological consequences of excess calorie intake that occur with metabolic syndrome and type 2 diabetes.

Public Health Relevance

This renewal focuses on the pathways responsible for uptake of lipids by tissues. We will specifically study endothelial transport of fatty acids and determine whether the primary source of fatty acids for muscle is derived from lipoprotein-transported triglyceride.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL045095-25A1
Application #
8886500
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Liu, Lijuan
Project Start
1991-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
25
Fiscal Year
2015
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
(2018) ATVB Named Lecture Reviews-Insight Into Author. Arterioscler Thromb Vasc Biol 38:707-708
Goldberg, Ira J (2018) 2017 George Lyman Duff Memorial Lecture: Fat in the Blood, Fat in the Artery, Fat in the Heart: Triglyceride in Physiology and Disease. Arterioscler Thromb Vasc Biol 38:700-706
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Drosatos, Konstantinos; Pollak, Nina M; Pol, Christine J et al. (2016) Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function. Circ Res 118:241-53

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