Adipose tissue plays a central role in lipid metabolism and the maintenance of energy homeostasis. Dysregulation of adipocyte development or function contributes to the pathogenesis of metabolic diseases including obesity, diabetes and atherosclerosis. The long-term goal of this Project is to understand the molecular pathways that control adipocyte differentiation and function, a goal which central to the overall theme of this PPG. Ultimately, elucidation of such pathways is expected to outline new opportunities for therapeutic intervention in human metabolic disease. The first Specific Aim is to define the function of novel transcription factors involved in triglyceride storage. We have utilized a high throughput screening approach to identify new genes that stimulate lipid accumulation in cell culture models of adipogenesis. Our initial focus will be on TLE3, a transcriptional corepressor with no previously recognized link to lipid metabolism. TLE3 is preferentially expressed in adipose tissue, is upregulated in murine models of obesity/diabetes, and is downregulated in lipodystrophic Lipinl-/- mice. We hypothesize that TLE3 acts through the direct regulation of adipocyte gene expression and that alterations in TLE3 activity may contribute to insulin resistance and/or obesity. We propose: (a) to identify target genes for TLE3, (b) to test the hypothesis that TLE3 serves as a cofactor for adipomodulatory transcription factors, (c) to determine the role of TLE3 in metabolism in vivo, and (d) to test the hypothesis that TLE3 and lipins cooperate in the control of adipocyte gene expression. The second Specific Aim is to identify the mechanism of action of small molecule regulators of adipogenesis. We have utilized high throughput screening to identify new small molecule inducers of lipid accumulation, including one compound, harmine, that regulates expression of the entire PPARy/lipin- 1/GPIHBP1 axis in vivo. Moreover, harmine has anti-diabetic activity in mice, validating our approach as a new strategy for the identification pharamcologic regulators of metabolism. We hypothesize that defining the molecular mechanism by which small molecules alter the adipogenic program will lead to the identification of new signaling pathways. We propose to: (a) map the cis-acting elements that mediate the activity of small molecules on the PPARy promoter, (b) identify mediators of small molecule action on adipogenesis, (c) test the hypothesis that small molecule regulators of PPARy expression comprise a novel class of pharmacologic regulators of lipid and glucose metabolism in vivo, (d) determine the mechanism whereby harmine regulates GPIHBP1 expression, and (e) to examine crosstalk between transcriptional pathways elucidated in Aim 1 and small molecule signaling pathways characterized in Aim 2.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL090553-03
Application #
8115986
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$474,394
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kristensen, Kristian K; Midtgaard, Søren Roi; Mysling, Simon et al. (2018) A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proc Natl Acad Sci U S A 115:E6020-E6029
Allan, Christopher M; Heizer, Patrick J; Jung, Cris J et al. (2018) Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice. J Dermatol Sci 89:85-87
He, Cuiwen; Weston, Thomas A; Jung, Rachel S et al. (2018) NanoSIMS Analysis of Intravascular Lipolysis and Lipid Movement across Capillaries and into Cardiomyocytes. Cell Metab 27:1055-1066.e3
Larsson, Mikael; Allan, Christopher M; Heizer, Patrick J et al. (2018) Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure. J Lipid Res 59:706-713
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Rajbhandari, Prashant; Thomas, Brandon J; Feng, An-Chieh et al. (2018) IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure. Cell 172:218-233.e17
He, Cuiwen; Hu, Xuchen; Weston, Thomas A et al. (2018) Macrophages release plasma membrane-derived particles rich in accessible cholesterol. Proc Natl Acad Sci U S A 115:E8499-E8508
He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) High-resolution imaging and quantification of plasma membrane cholesterol by NanoSIMS. Proc Natl Acad Sci U S A 114:2000-2005
Allan, Christopher M; Tran, Deanna; Tu, Yiping et al. (2017) A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency. Exp Dermatol 26:1134-1136
Larsson, Mikael; Allan, Christopher M; Jung, Rachel S et al. (2017) Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL. J Lipid Res 58:1893-1902

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