PNPLA3 I148M is involved in the variability in anti-NAFLD response to exenatide
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ORIGINAL ARTICLE
PNPLA3 I148M is involved in the variability in anti-NAFLD response to exenatide Yunzhi Chen1 Xuemei Yan2 Xiao Xu1 Shuhua Yuan3 Fen Xu1 Hua Liang1 ●
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Received: 16 May 2020 / Accepted: 19 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose GLP-1 receptor agonists, such as exenatide, have been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. However, the efficiency of exenatide had interindividual differences. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of the NAFLD spectrum. Whether this variant contributes to variability in exenatide response is still unclear. Methods PNPLA3 148I knockin HepG2 cells were constructed using the Cas9/sgRNA system. Oil Red O staining combined with TG quantification was used to evaluate lipid accumulation. Western blotting and qRT-qPCR were conducted, respectively, to measure the protein and mRNA expression of lipid metabolic and endoplasmic reticulum (ER) stress-related inflammatory markers. PNPLA3 I148M was genotyped in type 2 diabetics using Sanger sequencing. The exenatide-induced changes in liver fat content and other clinical parameters were compared between PNPLA3 I148M genotypes. Results Lipid deposition increased in both PNPLA3 148I/I and 148M/M HepG2 cells treated with palmitoleic acid, while cells with 148M/M had a higher TG content than those with 148I/I. Exendin-4 treatment was showed to be more significant in 148I/I cells than in 148M/M cells in terms of reducing the intrahepatic fat content, inhibiting SREBP-1c and ER stressrelated inflammation, and activating AMPK-ACC lipid oxidation pathway. In patients with type 2 diabetes, 24-week treatment with exenatide improved liver fat content in patients carrying PNPLA3 148I/I better than in patients with 148M/M. Conclusions PNPLA3 I148M might modify the anti-NAFLD response to exenatide. Keywords NAFLD PNPLA3 I148M GLP-1 receptor agonist Liver fat content Type 2 diabetes ●
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Abbreviations NAFLD Nonalcoholic fatty liver disease T2DM Type 2 diabetes mellitus PNPLA3 Patatin-like phospholipase domain protein 3 PA palmitate
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TG ER SREBP-1c Bip JNK ACC AMPK
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Triglyceride Endoplasmic reticulum Sterol regulatory element binding protein 1 Binding protein Jun N-terminal kinase Acetyl CoA carboxylase AMP-activated protein kinase
These authors contributed equally: Yunzhi Chen, Xuemei Yan Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-020-02470-7) contains supplementary material, which is available to authorized users. * Hua Liang [email protected] 1
Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
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Department of Endocrinology and Metabolism, No. 903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
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Department of Endocrinology, Guangzhou Panyu Ce
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