title: TRC8 downregulation contributes to the development of non-alcoholic steatohepatitis by exacerbating hepatic endoplasmic reticulum stress.
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 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.
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: pochiao@ibms.sinica.edu.tw.
authors: Po-Chiao
authors: PC
authors: Chang
authors: Department of Pathology, National Cheng-Kung University Hospital, Tainan, Taiwan. Electronic address: hungwen@mail.ncku.edu.tw.
authors: Hung-Wen
authors: HW
authors: Tsai
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: tubulin@ibms.sinica.edu.tw.
authors: Ming-Tsai
authors: MT
authors: Chiang
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: plhinlord@gmail.com.
authors: Pei-Ling
authors: PL
authors: Huang
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: skshue@ibms.sinica.edu.tw.
authors: Song-Kun
authors: SK
authors: Shyue
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: lyc@ibms.sinica.edu.tw.
authors: Lee-Young
authors: LY
authors: Chau
keywords: Apoptosis; E3 ligase; ER stress; Nonalcoholic fatty liver disease; Unfolded protein response