Obesity and its fatal sequelae are among the most prevalent and challenging morbidities confronting the medical profession in the 21^^ century. Obesity leads to insulin resistance, hyperglycemia, and dyslipidemia. To lower blood glucose, the pancreas produces excess insulin which stimulates the liver to convert excess glucose to FAs and TGs. The increased FAs produce two potentially fatal sequelae: 1) elevated plasma lipids and atherosclerosis, leading to death from myocardial infarction or stroke; and 2) fatty liver, which can lead to death from cirrhosis and liver failure. The burden of these FA-related complications is enormous. More than half of the deaths in obese type 2 diabetics are attributable to cardiovascular disease (1). Moreover, more than one-third of the US population accumulates excess TGs in liver (2) a condition known as non-alcoholic fatty liver disease (NAFLD), which accounts for 10% of the liver transplants in the US (3). If we are to combat the deadly consequences of excess FA synthesis, we must understand the regulatory factors that trigger this response. Our Program Project Grant made an important start with two discoveries: 1) that SREBP-lc is the key protein mediating insulin stimulation of FA synthesis in the liver;and 2) that an SREBP-lc target gene, MIG12, encodes a protein that markedly stimulates the activity of acetyl-CoA carboxylase (ACC), the first committed enzyme in FA synthesis. If we successfully complete the studies outlined in Research Project 3, we will have laid the basis for a new strategy to prevent the excess synthesis of FAs, and ameliorate the fatal consequences of obesity and diabetes.

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)
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
Liu, Jingjing; Moon, Young-Ah (2016) Simple Purification of Adeno-Associated Virus-DJ for Liver-Specific Gene Expression. Yonsei Med J 57:790-4
Smagris, Eriks; Gilyard, Shenise; BasuRay, Soumik et al. (2016) Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins. J Biol Chem 291:10659-76
Hwang, Seonghwan; Hartman, Isamu Z; Calhoun, Leona N et al. (2016) Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver. J Biol Chem 291:13479-94
Schumacher, Marc M; Jun, Dong-Jae; Jo, Youngah et al. (2016) Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. J Lipid Res 57:1286-99
Tian, Jing; Goldstein, Joseph L; Brown, Michael S (2016) Insulin induction of SREBP-1c in rodent liver requires LXRα-C/EBPβ complex. Proc Natl Acad Sci U S A 113:8182-7
Theodoropoulos, Panayotis C; Gonzales, Stephen S; Winterton, Sarah E et al. (2016) Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat Chem Biol 12:218-25
Bartuzi, Paulina; Billadeau, Daniel D; Favier, Robert et al. (2016) CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat Commun 7:10961
Lee, Jyh-Yeuan; Kinch, Lisa N; Borek, Dominika M et al. (2016) Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533:561-4
Chen, Qiuyue; Denard, Bray; Lee, Ching-En et al. (2016) Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Mol Cell 63:567-78
Zhang, Yinxin; Lee, Kwang Min; Kinch, Lisa N et al. (2016) Direct Demonstration That Loop1 of Scap Binds to Loop7: A CRUCIAL EVENT IN CHOLESTEROL HOMEOSTASIS. J Biol Chem 291:12888-96

Showing the most recent 10 out of 727 publications