Obesity and associated diseases, such as diabetes and hepatic steatosis, are characterized by excessive amounts of triglycerides (TGs) in tissues. To develop therapies for these diseases, an understanding of the molecular processes involved in the synthesis and storage of TGs is crucial. However, our understanding of the molecular and physiological aspects of TG metabolism is incomplete. The final and only committed step in triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Mammals possess two DGAT enzymes, DGAT1 and DGAT2, which differ substantially in their biochemical and physiological functions. The current proposal addresses fundamental questions about DGAT enzymes at the biochemical, cellular, and physiological levels by pursuing three specific aims.
Aim 1 focuses on elucidating the posttranslational regulation of DGAT1 by phosphorylation.
Aim 2 focuses on elucidating physiological functions of DGAT1 by using murine genetic models with inactivation of the enzyme in specific tissues or cells relevant to fat metabolism, such as the adipose tissue, small intestine, and macrophages.
Aim 3 investigates an intriguing idea of manipulating DGAT expression in induced pluripotent stem (iPS) cells as a potential therapy for type 2 diabetes associated with obesity. Work resulting from these aims will advance the field of lipid synthesis as it relates to obesity. Because both DGAT enzymes are prospective targets of pharmaceutical approaches to treat obesity, diabetes, and hepatic steatosis, our studies also may have significant impact on the treatment of these diseases.

Public Health Relevance

Obesity and related diseases, such as diabetes, occur when there is an overload of triglycerides in the fat and other tissues. This grant focuses on studying all aspects of the basic biology of the enzymes (called DGATs) that make triglycerides. Since DGAT enzymes are drug targets for treating or preventing obesity, diabetes, and related disorders of triglyceride metabolism, these studies are of great relevance to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056084-12
Application #
8541000
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Pawlyk, Aaron
Project Start
2000-05-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2013
Total Cost
$516,290
Indirect Cost
$245,981
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Klemm, Robin W; Norton, Justin P; Cole, Ronald A et al. (2013) A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Rep 3:1465-75
Krahmer, Natalie; Farese Jr, Robert V; Walther, Tobias C (2013) Balancing the fat: lipid droplets and human disease. EMBO Mol Med 5:905-15
Shimazu, Tadahiro; Hirschey, Matthew D; Newman, John et al. (2013) Suppression of oxidative stress by *-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339:211-4
Currie, Erin; Schulze, Almut; Zechner, Rudolf et al. (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153-61
Camus, Gregory; Herker, Eva; Modi, Ankit A et al. (2013) Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core. J Biol Chem 288:9915-23
Streeper, Ryan S; Grueter, Carrie A; Salomonis, Nathan et al. (2012) Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice. Aging (Albany NY) 4:13-27
Harris, Charles; Herker, Eva; Farese Jr, Robert V et al. (2011) Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis. J Biol Chem 286:42615-25
Harris, Charles A; Haas, Joel T; Streeper, Ryan S et al. (2011) DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J Lipid Res 52:657-67
Herker, Eva; Harris, Charles; Hernandez, Celine et al. (2010) Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 16:1295-8
Shih, Michelle Y S; Kane, Maureen A; Zhou, Ping et al. (2009) Retinol Esterification by DGAT1 Is Essential for Retinoid Homeostasis in Murine Skin. J Biol Chem 284:4292-9

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