INVESTIGATION OF THE ROLES OF NUCLEAR RECEPTOR FXR IN HEPATOCELLULAR

描述（由申请人提供）：法内甾体X受体（FXR, NR1H4）属于核受体超家族，是肝脏代谢的关键代谢调节剂，包括胆汁酸（BA）、脂质和葡萄糖代谢。我们最近证明，随着年龄的增长，FXR-/-小鼠自发地产生了肝脏肿瘤，小鼠表现出明显的肝损伤、炎症和不规则的再生。这些结果提示FXR在抑制肝细胞癌（HCC）中的新作用。肝细胞癌仍然是世界范围内癌症死亡的主要原因，在包括美国在内的发达国家，肝细胞癌的发病率正在上升。虽然有多种HCC动物模型，但FXR-/-小鼠为研究HCC的发生机制，特别是肝脏代谢与肝癌发生的病因学联系提供了独特的病理相关模型。FXR-/-小鼠肝细胞癌的发生与人类肝细胞癌的病理进展相似，因此，更好地了解FXR在肝细胞癌中的作用将有助于我们发现新的靶点，为肝细胞癌的预防和治疗提供新的途径。根据我们之前的工作和更多的初步数据，我们假设FXR是一种新的肝保护和HCC抑制因子。具体来说，FXR调节超氧化物歧化酶（EC-SOD, SOD3）和其他抗氧化应激基因的表达，这些基因抑制活性氧（ROS）的有害作用，并防止肝脏中JNK1的长时间激活。FXR也直接调节抗凋亡通路基因的表达，FXR功能障碍导致细胞死亡和肝损伤加剧，从而促进HCC的发展。我们在这个建议中提出了两个具体目标。在第一个Aim中，我们将定义FXR在ROS代谢和JNK1激活中的作用及其与HCC发展的联系。在第二个目标中，我们将确定FXR在调节抗凋亡基因表达中的作用。这些实验方法将有助于我们更好地了解FXR在HCC中的作用，并为人类肝癌的发生提供见解。这项工作具有创新性，因为这项研究将定义肝脏代谢与HCC之间的新联系。这些研究的成功完成将导致HCC预防和治疗新方法的发展。

DESCRIPTION (provided by applicant): Farnesoid X Receptor (FXR, NR1H4) belongs to nuclear receptor superfamily and is a key metabolic regulator in liver metabolism, including bile acid (BA), lipid and glucose metabolism. We recently demonstrated that FXR-/- mice spontaneously developed liver tumors as they aged and the mice displayed prominent liver injury, inflammation and irregular regeneration. These results suggest a novel role of FXR in suppressing hepatocellular carcinoma (HCC). HCC remains a major cause of cancer death worldwide, and the incidence of HCC in developed countries, including the United States, is increasing. Although there are several animal models of HCC, FXR-/- mice provide a unique pathologically relevant model to study the mechanism of HCC development, especially the etiological connection between liver metabolism and hepatocarcinogenesis. The development of HCC in FXR-/- mice mimics the pathological progression of human HCC, therefore, better understanding the roles of FXR in HCC will help us to identify new targets and provide novel approaches for HCC prevention and therapy. Based on our previous work and more preliminary data accompanying this proposal, we hypothesize that FXR is a novel liver protector and HCC suppressor. Specifically, FXR regulates the expression of a superoxide dismutase (EC-SOD, SOD3) and other anti-oxidative stress genes that suppress the deleterious effect of reactive oxygen species (ROS) and prevents prolonged JNK1 activation in liver. FXR also directly modulates the expression of genes in anti-apoptosis pathways, and that dysfunction of FXR results in enhanced cell death and liver injury, thereby promoting the HCC development. We propose two Specific Aims in this proposal. In the first Aim, we will define the roles of FXR in ROS metabolism and JNK1 activation and their link to HCC development. In the second Aim, we will determine the roles of FXR in regulating the expression of anti-apoptotic genes. These experimental approaches will help us better understand the roles of FXR in HCC and provide insight into the human hepatocarcinogenesis. The proposed work is innovative as the proposed studies will define a novel link between liver metabolism and HCC. Successful completion of the proposed studies will lead to the development of novel approaches for the prevention and treatment of HCC.