EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner

Kuangyang Chen; Yahao Wang; Jia Yang; Nora Klöting; Chuanfeng Liu; Jiarong Dai; Shuoshuo Jin; Lijiao Chen; Shan Liu; Yuzhao Liu; Yongzhuo Yu; Xiaoxia Liu; Qing Miao; Chong Wee Liew; Yangang Wang; Arne Dietrich; Matthias Blüher; Xuanchun Wang

doi:10.1016/j.jhep.2024.03.047

EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner

J Hepatol. 2024 Apr 8:S0168-8278(24)00234-4. doi: 10.1016/j.jhep.2024.03.047. Online ahead of print.

Authors

Kuangyang Chen¹, Yahao Wang², Jia Yang², Nora Klöting³, Chuanfeng Liu⁴, Jiarong Dai², Shuoshuo Jin², Lijiao Chen², Shan Liu², Yuzhao Liu⁴, Yongzhuo Yu⁴, Xiaoxia Liu², Qing Miao², Chong Wee Liew⁵, Yangang Wang⁴, Arne Dietrich⁶, Matthias Blüher³, Xuanchun Wang⁷

Affiliations

¹ Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
³ Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
⁴ Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁵ Department of Physiology & Biophysics, University of Illinois at Chicago, Chicago, IL, USA.
⁶ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany.
⁷ Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: wangxch@fudan.edu.cn.

PMID: 38599383
DOI: 10.1016/j.jhep.2024.03.047

Abstract

Background & aims: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in MASLD.

Methods: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD.

Results: scEMC10 promoted, while mEMC10 suppressed the activation of hepatocytic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated hepatic ER stress and steatosis in mice challenged with either a MCD diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented hepatosteatosis in mice with fatty liver, suggesting a progressive role of scEMC10 in MASLD. Clinically, serum scEMC10 increased, while hepatic mEMC10 decreased in participants with MASLD. Correlative analysis indicated serum scEMC10 positively, whereas hepatic mEMC10 negatively correlated with liver fat content and serum ALT, AST, and GGT.

Conclusions: These findings demonstrate a novel, isoform specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization.

Impact and implications: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic ER stress and steatosis in mice, and associations of MASLD with different EMC10 isoforms in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies clearly provide the foundations for translation of scEMC10 modulation for the treatment of MASLD.

Keywords: ER stress; MASLD; PERK-eIF2α-ATF4 signaling; hepatosteatosis; membrane-bound EMC10; secreted EMC10.