PROJ 3: ROLE OF SHP IN FATTY LIVER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 目前的肥胖流行导致代谢综合征的急剧增加，这经常导致脂肪肝，这可能导致纤维化，肝硬化和终末期肝病。肥胖影响了64%的美国人口，每年导致30万人死亡。与肥胖相关的脂肪肝（脂肪变性）影响超过50%的50岁以上的人。这些研究的目的是了解孤儿核受体小异源二聚体伴侣（SHP）在与脂肪肝相关的血脂异常的分子机制中所起的作用。在SHP缺失小鼠中消除SHP信号传导可防止高胆固醇或高脂肪饮食诱导的肝脏脂肪变性和肥胖。有趣的是，瘦素缺陷型肥胖小鼠（OB/OB）的脂肪肝也可以通过缺乏SHP（OB/SHP-双无效小鼠）来预防。这为探讨SHP在脂肪肝形成中的作用提供了一种独特的动物模型。待检验的假设是SHP的功能是调节脂质代谢中关键步骤的表达，并且SHP调节的途径对于脂肪肝的发展是必不可少的。为了检验这一假设，将解决以下具体目标：1）确定在OB/SHP缺失小鼠中是否发生血清甘油三酯清除率和肝脂质摄取降低或肝VLDL产生增加; 2）表征参与脂蛋白转运的基因的表达（例如，3）确定SHP调控的肝脏脂质代谢途径中的靶基因，并检测SHP对这些基因的转录调控，以确定其预防OB/SHP基因敲除小鼠脂肪肝的机制。确定SHP的特定功能和解释OB/SHP缺失小鼠脂肪肝预防的潜在机制，将为理解和预防患者肥胖相关脂肪肝提供机制见解和新方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The current obesity epidemic is resulting in a dramatic increase in the metabolic syndrome, that frequently results in fatty liver, which can cause fibrosis, cirrhosis, and end-stage liver disease. Obesity affects 64% of the U.S. population and results in 300,000 deaths every year. Fatty liver (steatosis) associated with obesity affects more than 50% of people over the age of 50. The goal of these studies is to understand the role that the orphan nuclear receptor small heterodimer partner (SHP) plays in the molecular mechanisms of dyslipidemias associated with fatty liver. Eliminating SHP signaling, in SHP-null mice, protects against a high cholesterol or high-fat diet induced liver steatosis and obesity. Intriguingly, the fatty liver in leptin deficient obese mice (OB/OB) was also prevented by the absence of SHP (OB/SHP-double-null mice). This provides a unique animal model to explore the function of SHP in fatty liver formation. The hypothesis to be tested is that SHP functions to modulate the expression of critical steps in lipid metabolism, and that SHP regulated pathways are essential for the development of fatty liver. To test this hypothesis, the following specific aims will be addressed: 1) Determine whether decreased serum triglyceride clearance and hepatic lipid uptake or increased hepatic VLDL production occurs in OB/SHP-null mice; 2) Characterize expression of genes involved in lipoprotein transport (e.g., VLDL production, HDL synthesis, triglyceride clearance, lipid uptake, and hepatic lipid synthesis) in OB/OB and OB/SHP-null mice to identify SHP target genes; 3) Identify SHPregulated-target genes in hepatic lipid metabolic pathways, and examine the transcriptional regulation of these genes by SHP, to determine the mechanism that prevents fatty liver in OB/SHP-null mice. Identifying the specific functions of SHP and the underlying mechanisms that account for the prevention of fatty liver in OB/SHP-null mice, will provide mechanistic insight and novel approaches to understanding and preventing obesity-associated fatty liver in patients.