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Chen, K.* ; Wang, Y.* ; Yang, J.* ; Klöting, N. ; Liu, C.* ; Dai, J.* ; Jin, S.* ; Chen, L.* ; Liu, S.* ; Liu, Y.* ; Yu, Y.* ; Liu, X.* ; Miao, Q.* ; Liew, C.W.* ; Dietrich, A.* ; Blüher, M. ; Wang, X.*

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

J. Hepatol. 81, 479-491 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Er Stress ; Masld ; Perk-eif2α-atf4 Signaling ; Hepatosteatosis ; Membrane-bound Emc10 ; Secreted Emc10; Endoplasmic-reticulum Stress; Liver; Methionine; Mechanisms; Obesity
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Zeitschrift Journal of Hepatology
Quellenangaben Band: 81, Heft: 3, Seiten: 479-491 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen Shandong Provincial Health Commission
Science and Technology Commission of Shanghai Municipality
National Natural Science Foundation of China