Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer

PloS One
Tianpeng ZhangAvraham Raz

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.

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Citations

Dec 28, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Na LiBao-Liang Song
Aug 30, 2017·Nature Reviews. Endocrinology·Hitoshi Shimano, Ryuichiro Sato
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Sep 12, 2017·Frontiers in Cellular Neuroscience·Vibhuti JoshiAmit Mishra
Dec 3, 2020·International Journal of Molecular Sciences·Maria Mercado-GómezTeresa C Delgado
Dec 6, 2020·International Journal of Molecular Sciences·Gyeongyun Go, Sang Hun Lee

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Methods Mentioned

BETA
immunoprecipitation
gene trap
PCR
protein folding

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