TRC8 downregulation contributes to the development of non-alcoholic steatohepatitis by exacerbating hepatic endoplasmic reticulum stress

Biochimica Et Biophysica Acta
Po-Chiao ChangLee-Young Chau

Abstract

Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). TRC8 is an ER-resident E3 ligase with roles in modulating lipid and protein biosynthesis. In this study we showed that TRC8 expression was downregulated in steatotic livers of patients and mice fed with a high fat diet (HFD) or a methionine and choline deficient (MCD) diet. To investigate the impact of TRC8 downregulation on steatosis and the progression to non-alcoholic steatohepatitis (NASH), we placed TRC8 knockout (KO) mice and wild type (WT) controls on a HFD or MCD diet and the severities of steatosis and NASH developed were compared. We found that TRC8 deficiency did not significantly affect diet-induced steatosis. Nevertheless, MCD diet-induced NASH as characterized by hepatocyte death, inflammation and fibrosis were exacerbated in TRC8-KO mice. The hepatic ER stress response, as evidenced by increased eIF2α phosphorylation and expression of ATF4 and CHOP, and the level of activated caspase 3, an apoptosis indicator, were augmented by TRC8 deficiency. The hepatic ER stress and NASH induced in mice could be ameliorated by adenovirus-mediated hepatic TRC8 overexpression. Mechanistically, we found that TRC8 defi...Continue Reading

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Citations

Sep 12, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Kai LiZhipeng Zou
Jun 15, 2021·Frontiers in Genetics·Jose Miguel Perez-Tejeiro, Fabiana Csukasi

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