Gp78, an E3 Ubiquitin Ligase Acts as a Gatekeeper Suppressing Nonalcoholic Steatohepatitis (NASH) and Liver Cancer

Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78-/- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors. Acute ER stress revealed that loss of gp78 results in up regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis, responsible for fatty liver. Tissue array of human hepatocellular carcinoma (HCC) demonstrated that the expression of gp78 was inversely correlated with clinical grades of cancer. Here, we have described the generation of the first preclinical experimental model system which spontaneously develops age-related NASH and HCC, linking ERAD to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver.

非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis, NASH）与代谢失调及内质网（endoplasmic reticulum, ER）稳态紊乱密切相关，且常进展为肝细胞癌（hepatocellular carcinoma, HCC）。Gp78是一种E3泛素连接酶（E3 ligase），可通过对错误折叠的内质网蛋白进行泛素化修饰，调控内质网相关降解（endoplasmic reticulum-associated degradation, ERAD）通路。本研究发现，当小鼠衰老至12月龄时，gp78基因敲除小鼠会出现肥胖表型，重现了与人类衰老相关的非酒精性脂肪性肝炎的病理特征。对gp78基因敲除小鼠的肝脏组织学检测显示，其出现典型的脂肪变性、肝脏炎症与纤维化，并进一步进展为肝细胞肿瘤。急性内质网应激实验表明，gp78的缺失会导致未折叠蛋白反应（unfolded protein response, UPR）通路以及调控从头脂肪生成的固醇调节元件结合蛋白-1（SREBP-1）的表达上调，这正是脂肪肝发生的核心机制。人类肝细胞癌组织芯片检测结果显示，gp78的表达水平与癌症临床分级呈负相关。本研究首次构建了可自发出现衰老相关非酒精性脂肪性肝炎与肝细胞癌的临床前实验模型系统，该模型将内质网相关降解与肝脂肪变性、肝硬化及癌症发生直接关联起来。该研究提示，gp78是维持肝脏正常稳态的关键调控因子，同时也是人类肝脏中的肿瘤抑制因子。