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

Po Chiao Chang, Hung Wen Tsai, Ming Tsai Chiang, Pei Ling Huang, Song Kun Shyue, Lee Young Chau

研究成果: Article同行評審

4 引文 斯高帕斯(Scopus)

摘要

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 deficiency augmented lipotoxic-stress-induced unfolded protein response in hepatocytes by attenuating the arrest of protein translation and the misfolded protein degradation. These findings disclose a crucial role of TRC8 in the maintenance of ER protein homeostasis and its downregulation in steatotic liver contributes to the progression of NAFLD.

原文English
頁(從 - 到)2339-2351
頁數13
期刊Biochimica et Biophysica Acta - Molecular Basis of Disease
1852
發行號11
DOIs
出版狀態Published - 2015 十一月 1

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 分子生物學

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