Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes. (January 2023)

• Record Type: Journal Article
• Authors: Gao, Rong; Wang, Heting; Li, Ting; Wang, Jin; Ren, Zhitao; Cai, Nan; Ai, Heying; Li, Shasha; Lu, Yan; Zhu, Yanhua; Shuai, Xintao; He, Xuemin; Shi, Guojun; Chen, Yanming
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: NAFLD -- ER stress -- MUP -- Insulin resistance -- Protein synthesis; ER endoplasmic reticulum -- NAFLD non-alcoholic fatty liver disease -- MUP major urinary protein -- HFD high-fat diet -- DMSO dimethyl sulfoxide -- TG triglyceride -- PERK PKR-like kinase -- IRE1α inositol-requiring enzyme 1α -- MS Mass spectrometry -- PCA Principal component analysis -- GSEA Gene set enrichment analysis -- FDR false discovery rate -- KEGG Kyoto encyclopedia of genes and genomese -- UPR unfolded protein response -- ERAD endoplasmic reticulum-associated protein degradation -- HMWs high- molecular-weight complexes; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106585
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Disturbed endoplasmic reticulum (ER) stress response driven by the excessive lipid accumulation in the liver is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Restoring metabolic homeostasis by targeting ER stress is a potentially therapeutic strategy for NAFLD. Here we aim to identify novel proteins or pathways involved in regulating ER stress response and therapeutic targets for alleviating NAFLD. Proteomic and transcriptomic analysis demonstrated that major urinary proteins (MUPs) were significantly reduced in the livers from NAFLD mouse models. Then we confirmed that MUP1, the major secreted form of MUPs, was reduced at mRNA and protein expression levels in hepatocytes both in vivo and in vitro under ER stress. We further illustrated that MUP1 protein levels in the urine were reduced in mice with NAFLD, which was reversed by GLP-1 receptor agonist treatment. To study the relationship between ER stress and MUP1 biology, our analysis demonstrated that MUP1 was misfolded and trapped in the ER under ER stress in vivo . Interestingly, we discovered that recombinant MUP1 treatment in hepatocytes increased calcium efflux from the ER, which resulted in transient ER stress response, including reduced protein synthesis. These responses facilitated the alleviation of chemical induced ER stress in hepatocytes, which was suggested as "pre-adaptive ER stress". Besides, recombinant MUP1 pretreatment also improved ER stress-induced insulin resistance in hepatocytes. Our findings revealed a novel and critical role of MUP1, and recombinant MUP1 or its potential derivates may serve as a promising therapeutic target for alleviating NAFLD. Graphical Abstract: Proposed working model. Hepatic ER homeostasis was disturbed in NAFLD. Hepatic ER stress caused MUP1 to form aggregates and be trapped in the ER, thus reducing the secretion of MUP1. Replenishing MUP1 in hepatocytes increased calcium efflux and induced pre-adaptive ER stress transiently, which facilitated hepatocytes to alleviate chemical-induced ER stress and ER stress-induced insulin resistance through inhibiting protein synthesis. ga1 Highlights: Majority of MUPs are significantly reduced in liver tissue, serum and urine in mouse models with NAFLD. Hepatic ER homeostasis is disturbed in mouse models with NAFLD. MUP1 protein expression and secretion are reduced under ER stress in hepatocytes. MUP1 treatment suppresses ER stress-induced insulin resistance by promoting pre-adaptive ER stress response in hepatocytes.