title: Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer.
abstract: 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.
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Tianpeng
authors: T
authors: Zhang
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Dhong Hyo
authors: DH
authors: Kho
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Ying
authors: Y
authors: Wang
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Yosuke
authors: Y
authors: Harazono
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Kosei
authors: K
authors: Nakajima
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Youming
authors: Y
authors: Xie
authors: Departments of Oncology and Pathology, Wayne State University School of Medicine and the Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors: Avraham
authors: A
authors: Raz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications*; D060285:Receptors, Autocrine Motility Factor / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C555002:Amfr protein, mouse; D060285:Receptors, Autocrine Motility Factor