Lipogenesis is exquisitely regulated by nutritional/hormonal status. 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, which is low in the fasted state, increases drastically with feeding. Increased insulin is largely responsible for the activation of FAS transcription. During the last grant period, we showed that USF works as a molecular switch by recruiting multiple proteins to the FAS promoter region. In the presence of insulin, USF interacts with DNA-PK and P/CAF for its phosphorylation and acetylation, respectively. USF also interacts with BAF60c which is first phosphorylated by aPKC upon feeding/insulin treatment, bridging other BAF subunits to form LipoBAF complex for chromatin remodeling for activation of the FAS gene. We showed this common mechanism governs transcription of FAS and various other lipogenic genes. Recently, we found a Mediator component, Med17 to interact with USF, which links USF to the preinitiation complex formation for FAS transcription. Furthermore, we started to examine key epigenetic regulation via dynamic CpG and histone demethylation for the transcriptional activation of FAS upon feeding/insulin treatment. We propose following specific aims in this application:
Aim 1 is to characterize Med17 interaction with USF and to examine its role in the FAS promoter activation. The significance of feeding/insulin-dependent Med17 phosphorylation will also be studied.
Aim 2 is to examine feeding/insulin dependent CpG demethylation at the FAS promoter region and the role of TET in demethylation for lipogenic gene activation.
Aim 3 is to examine the function and phosphorylation of the histone demethylase that we found to interact with USF for histone modification and lipogenic gene activation. Finally, Aim 4 is to examine the in vivo roles in lipogenesis by adenovirus mediated shRNA knockdown and overexpression of these enzymes and their phosphorylation mutants in livers of mice. We will study the metabolic consequences, such as hepatic lipogenesis, triglyceride levels, blood lipid levels, and lipid metabolism, which may affect insulin sensitivity. Overall, this research will shed light on how lipogenic genes are activated by feeding/insulin treatment. It may also provide new therapeutic target(s) for metabolic diseases associated with dysregulation of fat metabolism, such as obesity, hepatosteatosis, and diabetes.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK081098-05A1
Application #
8962974
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2008-04-01
Project End
2019-06-30
Budget Start
2015-07-16
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
$344,892
Indirect Cost
$119,892
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Wang, Yuhui; Wong, Roger H F; Tang, Tianyi et al. (2013) Phosphorylation and recruitment of BAF60c in chromatin remodeling for lipogenesis in response to insulin. Mol Cell 49:283-97
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Wong, Roger H F; Chang, Inhwan; Hudak, Carolyn S S et al. (2009) A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136:1056-72