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

摩尔实验室发现，新的受体LRH-1（NR 5A 2）的特异性激活 激动剂配体二月桂酰磷脂酰胆碱（DLPC）有效减少肝脂肪变性， 小鼠模型的胰岛素敏感性。因此，LRH-1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，这种LRH- 1介导的途径对甲基库和一碳代谢的变化敏感， 介导令人兴奋的，但长期被忽视的抗脂肪变性作用的磷脂酰胆碱（PC）和膳食甲基 捐助者补充。发表的和我们的额外的初步结果，包括功能和 生物信息学研究证明LRH-1和SRC-2之间的高度显著的功能相互作用。在 与此雅阁，LRH-1激活的表型效应与之重叠，但与之相反 与肝脏SRC-2功能丧失相关。基于这些令人信服的结果， SRC-2是LRH-1激活在细胞中的有益作用的重要介质。 代谢综合征三个具体的目标将剖析的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，并与关键修饰剂SHP和AMP激酶。2）：定义调制的影响 甲基库对SRC-2活性和PTM的影响，特别是SRC-2甲基化变化的可能性 介导对一碳代谢改变的代谢反应。3)确定肝脏的影响- 特异性SRC-2基因敲除对DLPC和磷脂酰胆碱补充在两种急性 正常小鼠的基因表达反应和胰岛素抵抗小鼠的抗糖尿病和抗脂肪代谢反应 小鼠 相关性（参见说明）： 这个项目将严格测试一个具体的预测的整体“主代谢假说”的功能 的SRC-2，并将提供新的见解潜在的治疗方法代谢综合征。

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.