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.
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.
|Mo, P; Zhou, Q; Guan, L et al. (2015) Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling. Oncogene 34:3935-45|
|Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9|
|Gibbs, Julie; Ince, Louise; Matthews, Laura et al. (2014) An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med 20:919-26|
|Dasgupta, Subhamoy; O'Malley, Bert W (2014) Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology. J Mol Endocrinol 53:R47-59|
|Reineke, Erin L; Benham, Ashley; Soibam, Benjamin et al. (2014) Steroid receptor coactivator-2 is a dual regulator of cardiac transcription factor function. J Biol Chem 289:17721-31|
|Qin, Jun; Lee, Hui-Ju; Wu, San-Pin et al. (2014) Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 124:5013-26|
|Stashi, Erin; Lanz, Rainer B; Mao, Jianqiang et al. (2014) SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell Rep 6:633-45|
|Motamed, Massoud; Rajapakshe, Kimal I; Hartig, Sean M et al. (2014) Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. Mol Endocrinol 28:395-405|
|Wang, Ying; Lonard, David M; Yu, Yang et al. (2014) Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res 74:1506-17|
|Lin, Shih-Chieh; Li, Yo-Hua; Wu, Meng-Hsing et al. (2014) Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab 99:E427-37|
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