SRC-2 Mediates the Preventative Effects of LRH-1 for NASH in Metabolic Disease

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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. RELEVANCE (See instructions): 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.