REGULATION OF LIPOGENESIS

Summary

Principal Investigator: Hei Sook Sul
Affiliation: University of California
Country: USA
Abstract: Lipogenesis is exquisitely regulated by nutritional/hormonal states. Fatty acid synthase (FAS) is a central enzyme in lipogenesis and is thought to be a rate-limiting step in long-term regulation. FAS transcription is low in the fasted state but increases dramatically with feeding. Increased insulin is largely responsible for the activation of FAS transcription. We showed that feeding/insulin increases SREBP-1c but that, by direct physical interaction, USF bound to the -65 E-box recruits SREBP to bind -150 SRE for activation of the FAS promoter. USF may be a molecular switch during the fasting/feeding and diabetes/insulin transitions. Using tandem affinity purification coupled with mass spectrometry (MS), we recently identified components of the USF holocomplex and found that different components participate in a fasting/feeding dependent manner. By MS analysis, we also detected a feeding- dependent specific site phosphorylation of USF as well as two adjacent sites of USF acetylation. In Aim 1, once we identify the components of the USF holocomplex, we will examine by chromatin immunoprecipitation differential binding of the various components of USF holocomplex to the FAS promoter in fasting/feeding and diabetes/insulin treatments and correlate binding with the FAS promoter activity and transcription. Transgenic mice carrying CAT gene driven by the various 5'-deletions and mutations of the FAS promoter will allow us to verify the binding sites. We will also characterize direct or indirect interactions of various factors with USF as well as the interacting domains. SiRNA- mediated knockdown experiments will demonstrate the significance of these factors in the regulation of the FAS promoter. In Aim 2, we will examine specific USF phosphorylation by DNA-dependent protein kinase (DNA-PK) as well as the signaling pathway leading to DNA-PK activation and thus USF phosphorylation. We will also examine specific acetylation/deacetylation of USF via recruitment of P/CAF or HDAC9, which may depend on phosphorylation state of USF. Functional consequences of phosphorylation/acetylation of USF on the regulation of the FAS promoter will be studied. Finally, we will examine posttranslational modifications of USF in vivo by adenovirus mediated gene transfer or by generating transgenic mice. We will also use DNA-PK deficient mice to test the role of DNA-PK for USF function and lipogenesis as well as glucose/insulin homeostasis. Our research will elucidate the USF function as a master regulator of lipogenesis during fasting/feeding and diabetes/insulin transitions and may reveal a novel insulin signaling pathway. PUBLIC HEALTH RELEVANCE Obesity is a major health problem causing metabolic syndrome and type II diabetes and the control of adiposity is a top priority in managing these diseases. Lipogenesis is critical for lipid accumulation and homeostasis in liver and adipose tissue. This research is to understand metabolic control of lipogenesis and dysregulation in diabetes and obesity and may provide new therapeutic targets.
Funding Period: ----------------2009 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. pmc Phosphorylation and recruitment of BAF60c in chromatin remodeling for lipogenesis in response to insulin
    Yuhui Wang
    Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
    Mol Cell 49:283-97. 2013
  2. pmc A role of DNA-PK for the metabolic gene regulation in response to insulin
    Roger H F Wong
    Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
    Cell 136:1056-72. 2009
  3. pmc The skinny on fat: lipolysis and fatty acid utilization in adipocytes
    Maryam Ahmadian
    Department of Nutritional Science and Toxicology, University of California, Berkeley, California 9472, USA
    Trends Endocrinol Metab 20:424-8. 2009
  4. pmc Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective
    Roger H F Wong
    Department of Nutritional Science and Toxicology, and Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA
    Curr Opin Pharmacol 10:684-91. 2010

Detail Information

Publications5

  1. pmc Phosphorylation and recruitment of BAF60c in chromatin remodeling for lipogenesis in response to insulin
    Yuhui Wang
    Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
    Mol Cell 49:283-97. 2013
    ..Consequently, BAF60c promotes lipogenesis in vivo and increases triglyceride levels, demonstrating its role in metabolic adaption to activate the lipogenic program in response to feeding and insulin...
  2. pmc A role of DNA-PK for the metabolic gene regulation in response to insulin
    Roger H F Wong
    Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
    Cell 136:1056-72. 2009
    ..Our study demonstrates that a kinase central to the DNA damage response mediates metabolic gene activation...
  3. pmc The skinny on fat: lipolysis and fatty acid utilization in adipocytes
    Maryam Ahmadian
    Department of Nutritional Science and Toxicology, University of California, Berkeley, California 9472, USA
    Trends Endocrinol Metab 20:424-8. 2009
    ..Here, we discuss the regulation of lipolysis and its effects on FA utilization within WAT and on insulin resistance...
  4. pmc Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective
    Roger H F Wong
    Department of Nutritional Science and Toxicology, and Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA
    Curr Opin Pharmacol 10:684-91. 2010
    ..Transcription factors and signaling molecules involved in transcriptional activation of FA and TAG synthesis represent attractive targets for the prevention and treatment of metabolic diseases...