Disorders associated with obesity represent some of the biggest medical challenges of this century. These disorders encompass hypertriglyceridemia, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), and diabetes. We have shown in animal models with insulin resistance that hypertriglyceridemia and NAFLD share the same underlying molecular alteration: elevated nuclear SREBP-1c, which leads to increased synthesis of fatty acids and triglycerides in the liver. Two SREBP isoforms exist in most organs, SREBP-1c and SREBP-2. Remarkably, feedback inhibition of cholesterol synthesis and feedback inhibition of fatty acid synthesis are mediated by inhibition of the proteolytic processing of SREBP-2 and SREBP-1c, respectively. Here, our goal is to delineate the molecular mechanism by which polyunsaturated fatty acids (PUFAs) mediate the feedback suppression of fatty acid synthesis by inhibiting the activation of SREBP-1.
AIM 1 will examine a fundamental unanswered question in regulation of lipogenesis, namely, how is SREBP-1c processing regulated independently from SREBP-2 despite using the same molecular machinery? These studies will define the specific region of SREBP-1 that is responsible for mediating PUFA inhibition of SREBP-1 cleavage and activation. We will use biochemical purification and somatic cell genetics to identify a putative protein that binds PUFAs and interacts with SREBP-1, but not SREBP-2, to prevent cleavage and activation. We will also define how PUFAs alter the membrane lipid composition of the endoplasmic reticulum and how these changes prevent SREBP-1 cleavage.
AIM 2 will investigate a recently discovered protein, Ubxd8, that binds and senses unsaturated fatty acids. We will determine whether PUFAs inactivate Ubxd8 in mouse livers and elucidate its role in regulating SREBP-1c processing in vivo.
AIM 3 will explore why inhibiting the first committed enzyme in fatty acid synthesis (acetyl-CoA carboxylase) prevents the development of fatty liver, even though this inhibition leads to activation of SREBP- 1c and hypertriglyceridemia. At its completion, RP 3 will elucidate new mechanisms that regulate SREBP activity and fatty acid synthesis in liver, thereby providing new therapeutic opportunities for treatment of hypertriglyceridemia and NAFLD. C/PPG 2015 ? RP3 ? 30-line Summary

Public Health Relevance

This Research Project is designed to gain a molecular understanding of how polyunsaturated fatty acids reduce the production of fatty acids and triglycerides in the liver. Our studies will focus on the biochemical actions of several proteins: a transcription factor that activates genes for fatty acid synthesis and a protein that senses the level of polyunsaturated fatty acids in cells. A molecular understanding of these molecules may lead to more effective drugs for the treatment of hypertriglyceridemia and fatty liver, a complication of obesity and diabetes. C/PPG 2015 ? RP3 ? Project Narrative

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
United States
Zip Code
Mitsche, Matthew A; Hobbs, Helen H; Cohen, Jonathan C (2018) Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 293:6958-6968
Banfi, Serena; Gusarova, Viktoria; Gromada, Jesper et al. (2018) Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice. Proc Natl Acad Sci U S A 115:E1249-E1258
Fine, Michael; Schmiege, Philip; Li, Xiaochun (2018) Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nat Commun 9:4192
Linden, Albert G; Li, Shili; Choi, Hwa Y et al. (2018) Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. J Lipid Res 59:475-487
Johnson, Brittany M; DeBose-Boyd, Russell A (2018) Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase. Semin Cell Dev Biol 81:121-128
Qi, Xiaofeng; Schmiege, Philip; Coutavas, Elias et al. (2018) Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex. Science 362:
Engelking, Luke J; Cantoria, Mary Jo; Xu, Yanchao et al. (2018) Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol 81:98-109
Hobbs, Helen H (2018) Science, serendipity, and the single degree. J Clin Invest 128:4218-4223
Muse, Evan D; Yu, Shan; Edillor, Chantle R et al. (2018) Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. Proc Natl Acad Sci U S A 115:E4680-E4689
DeBose-Boyd, Russell A; Ye, Jin (2018) SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond. Trends Biochem Sci 43:358-368

Showing the most recent 10 out of 766 publications