Metabolic syndrome is emerging as a global epidemic. The profound metabolic dysregulation in this syndrome is typically manifested by clustering of several disorders, including obesity, type 2 diabetes, and dyslipidemia, and is associated with an increased risk for cardiovascular disease. Hepatic lipogenesis and lipoprotein metabolism are important in maintaining lipid homeostasis. There is increasing evidence that hepatic lipid metabolism plays an important role in the pathogenesis of key aspects of metabolic syndrome, including hyperlipidemia, hyperglycemia, and insulin resistance. We have recently demonstrated that transcriptional coactivator PGC-1? coordinately regulates lipogenesis, lipid trafficking, and lipoprotein metabolism in the liver. These data suggest that PGC-1? is a central component of the regulatory network in maintaining lipid homeostasis. The major goals of this proposal are to test the hypothesis that PGC-1? is involved in the pathogenesis of metabolic syndrome and serves as a molecular link between lipid metabolism and insulin resistance. In addition, molecular components of the PGC-1? pathway will be dissected and analyzed.
Aim 1 is to determine evaluate the role of PGC-1? in the pathogenesis of metabolic dysregulation and in linking lipid metabolism to insulin resistance.
Aim 2 is to define transcriptional components underlying PGC-1? regulation of triglyceride and lipoprotein metabolism.
Aim 3 is to investigate the role of chromatin remodeling in lipid metabolism. Completion of this proposal will define the molecular details of a major regulatory network in the maintenance of lipid homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077086-03
Application #
7647080
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Margolis, Ronald N
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$271,499
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Li, S; Lin, J D (2015) Transcriptional control of circadian metabolic rhythms in the liver. Diabetes Obes Metab 17 Suppl 1:33-8
Meng, Zhuo-Xian; Wang, Lin; Chang, Lin et al. (2015) A Diet-Sensitive BAF60a-Mediated Pathway Links Hepatic Bile Acid Metabolism to Cholesterol Absorption and Atherosclerosis. Cell Rep 13:1658-69
Ma, Di; Liu, Tongyu; Chang, Lin et al. (2015) The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis. J Biol Chem 290:31003-12
Zhao, Xu-Yun; Lin, Jiandie D (2015) Long Noncoding RNAs: A New Regulatory Code in Metabolic Control. Trends Biochem Sci 40:586-596
Zhao, Xu-Yun; Li, Siming; Wang, Guo-Xiao et al. (2014) A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol Cell 55:372-82
Wang, Guo-Xiao; Cho, Kae Won; Uhm, Maeran et al. (2014) Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation. Diabetes 63:1340-52
Cui, Shuaiying; Tanabe, Osamu; Lim, Kim-Chew et al. (2014) PGC-1 coactivator activity is required for murine erythropoiesis. Mol Cell Biol 34:1956-65
Xu, Guan; Meng, Zhuo-Xian; Lin, Jiandie D et al. (2014) The functional pitch of an organ: quantification of tissue texture with photoacoustic spectrum analysis. Radiology 271:248-54
Meng, Zhuo-Xian; Wang, Lin; Xiao, Yuanyuan et al. (2014) The Baf60c/Deptor pathway links skeletal muscle inflammation to glucose homeostasis in obesity. Diabetes 63:1533-45

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