Hepatic Lipid Mobilization by Nuclear Hormone Receptors

描述(申请人提供)：肝脏脂肪变性与非酒精性脂肪性肝病(NAFLD)有关，可发展为非酒精性脂肪性肝炎(NASH)。非酒精性脂肪肝也是空腹血糖受损和2型糖尿病的主要危险因素。小分子异二聚体(SHP，NR0B2)属于核激素受体超家族。早期的分子研究表明，SHP在糖脂代谢中发挥作用。我们用SHP-/-小鼠进行的研究表明，SHP调节肝脏甘油三酯(TG)的储存，以应对过量的膳食脂肪摄入，而SHP的不足则防止肝脏脂肪变性的发生。这种对SHP-/-小鼠脂肪肝发展的保护作用部分是由于PPAR？转录活性，但也降低了PPAR？2的表达，PPAR？2是主要的生脂转录因子。肝脏PPAR显著升高？在NAFLD的许多小鼠模型和患有这种疾病的人类患者中都观察到了这种表达。结合我们自己的初步结果和已发表的研究，我们已经确定了一个新的转录级联，其中SHP调节PPAR？表情。在这个新的调控途径中，SHP抑制维甲酸受体(RAR)激活转录辅阻遏子Hes6表达的能力，Hes6是最近报道的通过抑制HNF4？激活。与此相一致，我们已经证明RAR被其天然配体全反式维甲酸(AtRA)激活，可以减轻肝脏脂肪变性。因此，我们假设SHP和atRA/RAR可以协同作用来调节肝脏的脂质积聚。为了严格测试我们所提出的调节级联反应的意义，我们将1)确定SHP和atRA在Hes6表达中的调节作用，然后2)研究SHP和atRA/RAR在调控NAFLD小鼠模型脂肪积累方面的功能相互作用，最后3)通过Hes6过表达或沉默来测试Hes6和脂肪动员之间的联系。我们对这个新的转录调控网络的研究将为肝脏脂肪变性的发展提供洞察力，并为预防和治疗一种疾病提供重要途径，这种疾病是代谢综合征发展的主要贡献因素。

DESCRIPTION (provided by applicant): Hepatic steatosis is associated with nonalcoholic fatty liver disease (NAFLD), which can progress to nonalcoholic steatohepatitis (NASH). NAFLD is also a leading risk factor for the development of impaired fasting glucose and type 2 diabetes. Small heterodimer partner (SHP, NR0B2) belongs to the nuclear hormone receptor superfamily. Earlier molecular studies suggested that SHP plays a role in glucose and lipid metabolism. Our studies with congenic SHP-/- mice showed that SHP regulates hepatic triglyceride (TG) storage in response to excess dietary fat ingestion, and its deficiency protects against development of hepatic steatosis. This protection against fatty liver development in SHP-/- mice results in part from elevated-fatty acid oxidation due to derepression of PPAR? transcriptional activity, but also to lower expression of PPAR?2, a major lipogenic transcription factor. Marked elevation of hepatic PPAR? expression has been observed in numerous mouse models of NAFLD and human patients with the disorder. Integrating our own preliminary results with published studies, we have identified a novel transcriptional cascade in which SHP regulates PPAR? expression. In this new regulatory pathway, SHP represses the ability of the retinoic acid receptor (RAR) to activate expression of hairy and enhancer split 6 (Hes6) a transcriptional corepressor that has recently been reported to repress PPAR?2 via inhibition of HNF4? transactivation. In accord with this, we have shown that RAR activation by its natural ligand all-trans retinoic acid (atRA) alleviates hepatic steatosis. Thus we hypothesize that SHP and atRA/RAR can function coordinately to regulate hepatic lipid accumulation. In order to critically test the significance o our proposed regulatory cascade, we will 1) define the regulatory role of SHP and atRA in the expression of Hes6, then 2) examine the functional interactions of SHP and atRA/RAR in modulating fat accumulation in mouse models of NAFLD, and finally 3) test the linkage between Hes6 and fat mobilization using Hes6 overexpression or silencing. Our studies of this novel transcriptional regulatory network will provide insights into the development of hepatic steatosis and crucial avenues into the prevention and treatment of a disorder that is a major contributor in the development of the metabolic syndrome.