The Moore laboratory found that specific activation of the nuclear receptor LRH-1 (NR5A2) by the novel agonist ligand dilauroyl phosphatidylcholine (DLPC) potently reduces hepatic steatosis and improves overall insulin sensitivity in mouse models. Thus, LRH-1 activation provides an attractive therapeutic approach to treating two of the primary pathologies of the Metabolic Syndrome. Preliminary results indicate that this LRH- 1 mediated pathway is sensitive to changes in methyl pools and one-carbon metabolism, and that LRH-1 mediates exciting, but long neglected anti-steatotic effects of phosphatidylcholine (PC) and dietary methyl donor supplementation. Published and our additional preliminary results, including both functional and bioinformatics studies, demonstrate a highly significant functional interaction between LRH-1 and SRC-2. In accord with this, the phenotypic effects of LRH-1 activation overiap with, but are opposite to those associated with loss of hepatic SRC-2 function. Based on these compelling results, the specific hypothesis of this project is that SRC-2 is an essential mediator of the beneficial effects of LRH-1 activation in the metabolic syndrome.
Three specific aims will dissect the molecular basis and physiological significance of the functional interactions of SRC-2 and LRH-1: 1) Define the functional interactions of LRH-1 and SRC-2 with each other, and with the key modifiers SHP and AMP kinase. 2): Define the impact of modulating methyl pools on SRC-2 activity and PTMs, particulariy the possibility that changes in SRC-2 methylation mediate metabolic responses to alterations in one carbon metabolism. 3) Determine the impact of a liver- specific SRC-2 knockout on the effects of DLPC and phosphatidylcholine supplementation in both acute gene expression responses in normal mice and the anti-diabetic and lipotropic responses in insulin resistant mice.

Public Health Relevance

This project will critically test a specific prediction of the overall """"""""master metabolic hypothesis"""""""" for the function of SRC-2, and will provide novel insights into potential therapeutic approaches for the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK059820-11A1
Application #
8419648
Study Section
Special Emphasis Panel (ZDK1-GRB-D (M1))
Project Start
Project End
Budget Start
2012-09-14
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$353,529
Indirect Cost
$127,632
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lee, Hui-Ju; Kao, Chung-Yang; Lin, Shih-Chieh et al. (2017) Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Sci Rep 7:3136
Rohira, Aarti D; Yan, Fei; Wang, Lei et al. (2017) Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells. Cancer Res 77:4293-4304
Xu, Y; Qin, L; Sun, T et al. (2017) Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene 36:1157-1166
Xu, Yong; O'Malley, Bert W; Elmquist, Joel K (2017) Brain nuclear receptors and body weight regulation. J Clin Invest 127:1172-1180
Zhao, Fei; Franco, Heather L; Rodriguez, Karina F et al. (2017) Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357:717-720
Yi, Ping; Wang, Zhao; Feng, Qin et al. (2017) Structural and Functional Impacts of ER Coactivator Sequential Recruitment. Mol Cell 67:733-743.e4
Xie, Xin; Wu, San-Pin; Tsai, Ming-Jer et al. (2017) The Role of COUP-TFII in Striated Muscle Development and Disease. Curr Top Dev Biol 125:375-403
Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer (2016) COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest 126:3929-3941
Wang, Lei; Lonard, David M; O'Malley, Bert W (2016) The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets. Horm Cancer 7:229-35
Wang, Leiming; Xu, Mafei; Qin, Jun et al. (2016) MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget 7:14673-83

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