Lipoprotein lipase (LpL), the primary enzyme responsible for the hydrolysis of triglyceride within lipoproteins, modulates plasma levels of all plasma lipoproteins and allows cellular uptake of fatty acids to be used for energy, storage, and structural lipids. This application has funded experiments that have used in vivo methods to define structure/function aspects of LpL biology and assess the effects of tissue specific LpL overexpression. More recently, the PI and his colleagues have produced tissue specific deletion of LpL to investigate the role(s) of this enzyme in heart and skeletal muscle, islet cells, and brain. In addition, funds from this grant were used to create mice with transgenic overexpression of diacylglycerol acyl transferase 1 (DGAT1) in heart and skeletal muscle, and to study animals with a genetic or pharmacologic deficiency of DGAT1. In our Preliminary Results we show the following: muscle overexpression of LpL on a knockout background, but not adipose-specific LpL deletion retards adipose tissue development and increases muscle mass;in the heart, lipid uptake pathways for VLDL and chylomicrons differ;DGAT1 deletion increases muscle mass and also dramatically reduces expression of lipid uptake and oxidation genes. This renewal contains experiments that seek to use modulation of LpL and DGAT1 as tools to understand the following: 1) how tissues deficient in LpL acquire circulating lipids and develop normal adipose triglyceride stores, 2) how muscle lipid metabolism alters skeletal muscle growth, 3) how extracellular and intracellular pools of lipid modulate fatty acid uptake and oxidation via actions of PPARs. The experiments will use novel genetically modified mice, cultured myocytes, and state of the art lipidomics.

Public Health Relevance

Excess calories leading to ectopic fat accumulation are a major cause of insulin resistant diabetes, non-alcoholic fatty liver disease, and some forms of cardiomyopathy. The pathways responsible for lipid uptake into tissues and how they are regulated are incompletely understood. Two circulating forms of fat, fatty acids and triglycerides within lipoproteins, enter cells by overlapping but distinct pathways. One objective of this research is to understand how fats get delivered to tissues and how in turn they regulate gene transcription and fatty acid oxidation. The eventual goal is to identify therapeutic targets to prevent obesity and ectopic fat deposition. In addition, by understanding how fat regulates genes it is likely that better drugs can be developed for treatment of hypertriglyceridemia and insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045095-23
Application #
8467003
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Liu, Lijuan
Project Start
1991-04-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
23
Fiscal Year
2013
Total Cost
$446,129
Indirect Cost
$169,030
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66
Abumrad, Nada A; Goldberg, Ira J (2016) CD36 actions in the heart: Lipids, calcium, inflammation, repair and more? Biochim Biophys Acta 1860:1442-9
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
Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J (2016) Lipid Use and Misuse by the Heart. Circ Res 118:1736-51
Stadler, Krisztian; Goldberg, Ira J; Susztak, Katalin (2015) The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr Diab Rep 15:40
Willecke, Florian; Yuan, Chujun; Oka, Kazuhiro et al. (2015) Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice. PLoS One 10:e0128996
Willecke, Florian; Scerbo, Diego; Nagareddy, Prabhakara et al. (2015) Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol 35:102-10
Drosatos, Konstantinos; Lymperopoulos, Anastasios; Kennel, Peter Johannes et al. (2015) Pathophysiology of sepsis-related cardiac dysfunction: driven by inflammation, energy mismanagement, or both? Curr Heart Fail Rep 12:130-40
Kang, Hyun Mi; Ahn, Seon Ho; Choi, Peter et al. (2015) Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 21:37-46
Nagareddy, Prabhakara R; Kraakman, Michael; Masters, Seth L et al. (2014) Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 19:821-35

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