Functional characterization of the orphan nuclear receptors TR2 and TR4 in the pathophysiology of hepatic steatosis and fibrosis

非酒精性脂肪性肝病（NAFLD）是世界范围内肝脏疾病的主要病因之一，也是终末期肝病和肝细胞癌的重要病因。其发病机制和进展与营养过剩和肥胖有关，但目前的治疗选择有限。由于核激素受体是强大的生理调节剂和理想的药物靶点，我们已经使用基因组方法来识别那些可能在饮食诱导的肝脂肪变性和纤维化中起作用的受体。这些研究揭示了TR2和TR4是控制肝脏代谢和疾病的新候选者。因此，我们建议应用小鼠遗传学和基因组学方法，结合代谢组学，蛋白质组学和详细的表型和组织学分析来功能表征这两个相关的转录因子。该建议还包括鉴定肝细胞中TR2和TR4控制的转录靶基因和代谢途径。

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide and an important cause of end-stage liver disease and hepatocellular carcinoma. Its pathogenesis and progression have been linked to overnutrition and obesity, but current therapeutic options are limited. Since nuclear hormone receptors are powerful physiological regulators as well as ideal drug targets, we have used genomic approaches to identify those receptors which may play a role during diet-induced hepatic steatosis and fibrosis. These studies have revealed TR2 and TR4 as novel candidates controlling liver metabolism and disease. We therefore propose to apply mouse genetics and genomics approaches together with metabolomics, proteomics and detailed phenotypic and histological analyses to functionally characterize these two related transcription factors. This proposal also includes the identification transcriptional target genes and metabolic pathways controlled by TR2 and TR4 in hepatocytes.