Our Program Project Grant (PPG), "New Molecules in Triglyceride Metabolism and Adipogenesis," is guided by a unifying theme-to understand mechanisms for triglyceride delivery to peripheral tissues, triglyceride synthesis, and adipogenesis. The topic of this PPG is highly relevant to obesity and hyperlipidemia, two public health problems that are central to the mission of the NHLBI. Working as a team over the past 5 years, the Project and Core Leaders of this PPG have studied new molecules with crucial roles in triglyceride delivery to cells, triglyceride synthesis within cells, and adipogenesis. These studies identified new regulators of lipid metabolism and adipogenesis and have uncovered new causes of human disease. For the next 5 years, our PPG team will be guided by the same objective-to understand the mechanisms underlying obesity and metabolic disease. This PPG is organized into three Component Projects and two Cores. Project 1, "Function of GPIHBP1 in Triglyceride Metabolism," will be led by Dr. Stephen G. Young. This project focuses on a novel endothelial cell protein, GPIHBP1, and its role in plasma triglyceride metabolism and the delivery of lipid nutrients to adipose tissue, heart, and skeletal muscle. Project 2, "Lipin Protein Family Interactions, Lipid Intermediates, and Disease," will be led by Dr Karen Reue. Dr. Reue's discovery of the lipin family of enzymes set the stage for new studies on the regulation of triglyceride synthesis and the control of adipogenesis. Project 3, "Novel Pathways for Triglyceride Storage and Adipogenesis," will be led by Dr. Peter Tontonoz. Dr. Tontonoz identified new molecules controlling lipid metabolism and adipogenesis, including TLE3 and IDOL (inducible degrader of the LDL receptor). Dr. Tontonoz will decipher mechanisms by which these new players in lipid metabolism affect adipogenesis. A "Mouse Model and Protein Expression Core" (Core A) will create new lines of genetically modified mice and will produce purified proteins for biochemical studies and antibody production. An "Administrative" Core (Core B) will facilitate the efforts by all three Component Projects, organize advisory board meetings, and ensure compliance with institutional and NIH guidelines.

Public Health Relevance

Our country faces an epidemic of hyperlipidemia, metabolic disease, and obesity-exacting a horrific toll on patients, families, and our nation's health care budget. The guiding objective for this PPG is to understand the molecular mechanisms that govern fuel delivery to cells, hyperlipidemia, triglyceride synthesis, and adipogenesis. Pursuing this objective should lead to new treatments for metabolic disease and obesity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL090553-06A1
Application #
8608032
Study Section
Special Emphasis Panel (ZHL1-PPG-R (O1))
Program Officer
Ershow, Abby
Project Start
2007-12-01
Project End
2018-11-30
Budget Start
2013-12-15
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$1,914,297
Indirect Cost
$610,732
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Bensadoun, André; Mottler, Charlene D; Pelletier, Chris et al. (2014) A new monoclonal antibody, 4-1a, that binds to the amino terminus of human lipoprotein lipase. Biochim Biophys Acta 1841:970-6
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Zhang, Peixiang; Verity, M Anthony; Reue, Karen (2014) Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle. Cell Metab 20:267-79
Adeyo, Oludotun; Allan, Bernard B; Barnes 2nd, Richard H et al. (2014) Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice. J Invest Dermatol 134:1589-98
Plengpanich, Wanee; Young, Stephen G; Khovidhunkit, Weerapan et al. (2014) Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain. J Biol Chem 289:19491-9
Jiang, Haibo; Goulbourne, Chris N; Tatar, Angelica et al. (2014) High-resolution imaging of dietary lipids in cells and tissues by NanoSIMS analysis. J Lipid Res 55:2156-66

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