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

摩尔实验室发现，新的核受体LRH-1(NR5A2)的特异性激活 激动剂配体二月桂酰磷脂酰胆碱(DLPC)有效地减轻肝脏脂肪变性并全面改善 小鼠模型中的胰岛素敏感性。因此，LRH-1的激活提供了一种有吸引力的治疗方法 治疗代谢综合征的两种主要病理。初步结果表明，该LRH- 1介导的途径对甲基库和一碳代谢的变化敏感，而LRH-1 介导磷脂酰胆碱(PC)和饮食甲基的兴奋但长期被忽视的抗脂肪变性作用 捐赠者补充。和我们的其他初步结果，包括功能和 生物信息学研究表明，LRH-1和SRC-2之间存在非常显著的功能相互作用。在……里面 与此一致，LRH-1激活的表型效应与之重叠，但与之相反 与肝脏SRC-2功能丧失有关。基于这些令人信服的结果，具体的假设 本项目认为SRC-2是LRH-1激活在血管内皮细胞中的有益作用的重要中介。 代谢综合征。三个具体的目标将剖析分子基础和生理意义 SRC-2和LRH-1的功能相互作用：1)定义LRH-1和SRC-2的功能相互作用 相互作用，并与关键修饰物SHP和AMP激酶结合。2)：定义调制的影响 甲基库对SRC-2活性和PTMS的影响，特别是SRC-2甲基化改变的可能性 调节对一种碳代谢变化的代谢反应。3)确定肝脏的影响- 特异性SRC-2基因敲除对DLPC和磷脂酰胆碱对急性心肌梗死患者的影响 正常小鼠的基因表达反应及胰岛素抵抗时的抗糖尿病和趋脂反应 老鼠。 相关性(请参阅说明)： 这个项目将严格测试对功能的总体“主代谢假说”的具体预测。 对SRC-2的研究，将为代谢综合征的潜在治疗方法提供新的见解。

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.