Hepatic Lipid Mobilization by Nuclear Hormone Receptors

描述（由申请人提供）：肝脂肪变性与非酒精性脂肪性肝病（NAFLD）相关，NAFLD可发展为非酒精性脂肪性肝炎（NASH）。NAFLD也是发展为空腹血糖受损和2型糖尿病的主要危险因素。小异二聚体伴侣（SHP, NR0B2）属于核激素受体超家族。早期的分子研究表明，SHP在葡萄糖和脂质代谢中起作用。我们对同源SHP-/-小鼠的研究表明，SHP调节肝脏甘油三酯（TG）的储存，以应对过量的饮食脂肪摄入，其缺乏可以防止肝脂肪变性的发生。这种对SHP-/-小鼠脂肪肝发展的保护部分是由于PPAR抑制导致的脂肪酸氧化升高。转录活性，还能降低PPAR？2、主要的脂肪生成转录因子。肝PPAR明显升高？在许多NAFLD小鼠模型和患有该疾病的人类患者中都观察到了表达。将我们自己的初步结果与已发表的研究相结合，我们已经确定了一个新的转录级联，其中SHP调节PPAR？表达式。在这种新的调控途径中，SHP抑制视黄酸受体（RAR）激活毛状和增强子分裂6 （Hes6）表达的能力，Hes6是一种转录辅助抑制因子，最近被报道抑制PPAR？2通过抑制HNF4？transactivation。与此一致，我们已经证明RAR被其天然配体全反式维甲酸（atRA）激活可以减轻肝脂肪变性。因此，我们假设SHP和atRA/RAR可以协同调节肝脏脂质积累。为了严格测试我们提出的调控级联的意义，我们将1)定义SHP和atRA在Hes6表达中的调节作用，然后2)在NAFLD小鼠模型中检查SHP和atRA/RAR在调节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与脂肪动员之间的联系。我们对这种新型转录调控网络的研究将为肝脂肪变性的发展提供见解，并为预防和治疗一种代谢综合征发展的主要因素的疾病提供重要途径。

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.