Tao M, Zhang LL, Zhou GH, Wang C, Luo X. Inhibition of metabotropic glutamate receptor-5 alleviates hepatic steatosis by enhancing autophagy via activation of the AMPK signaling pathway. World J Gastroenterol 2025; 31(7): 98852 [DOI: 10.3748/wjg.v31.i7.98852]
Corresponding Author of This Article
Xie Luo, Doctor, MD, PhD, Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing 400010, China. 304408@hospital.cqmu.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Feb 21, 2025; 31(7): 98852 Published online Feb 21, 2025. doi: 10.3748/wjg.v31.i7.98852
Inhibition of metabotropic glutamate receptor-5 alleviates hepatic steatosis by enhancing autophagy via activation of the AMPK signaling pathway
Min Tao, Li-Li Zhang, Guang-Hong Zhou, Cong Wang, Xie Luo
Min Tao, Li-Li Zhang, Guang-Hong Zhou, Cong Wang, Xie Luo, Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
Author contributions: Tao M performed the majority of the experiments and contributed to the analysis of the data and the drafting of the manuscript; Zhou GH contributed to the analysis of the data; Zhang LL and Wang C revised and approved the final version of the manuscript; Luo X contributed to the study design, the drafting of the manuscript, and critical discussion and approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 81800771 and No. 81300702.
Institutional review board statement: The study was reviewed and approved by the Second Affiliated Hospital of Chongqing Medical University Institutional Review Board [Approval No. 2018(51)].
Institutional animal care and use committee statement: This study protocol was reviewed and approved by the Animal Care and Use Ethics Committee of Chongqing Medical University, Chongqing, China (protocol approval number: IACUC-CQMU-2024-0085).
Conflict-of-interest statement: All the authors have no conflicts of interest related to the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xie Luo, Doctor, MD, PhD, Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing 400010, China. 304408@hospital.cqmu.edu.cn
Received: July 7, 2024 Revised: December 8, 2024 Accepted: December 26, 2024 Published online: February 21, 2025 Processing time: 196 Days and 15.5 Hours
Abstract
BACKGROUND
The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has continued to increase annually. Recent studies have indicated that inhibition of metabotropic glutamate receptor 5 (mGluR5) may alleviate hepatic steatosis. However, the precise mechanism warrants further exploration.
AIM
To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.
METHODS
Free fatty acids (FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG. Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content. Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II, as well as the expression of the key signaling molecules AMPK and ULK1, in the treated cells. To further elucidate the contributions of autophagy and AMPK, we used chloroquine (CQ) to inhibit autophagy and compound C (CC) to inhibit AMPK activity. In parallel, wild-type mice and mGluR5 knockout (KO) mice fed a normal chow diet or a high-fat diet (HFD) were used to evaluate the effect of mGluR5 inhibition in vivo.
RESULTS
mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression. The autophagy inhibitor CQ reversed the effects of MPEP. In addition, MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs. MPEP treatment led to the nuclear translocation of transcription factor EB, which is known to promote p62 expression. This effect was negated by the AMPK inhibitor CC. mGluR5 KO mice presented reduced body weight, improved glucose tolerance and reduced hyperlipidemia when fed a HFD. Additionally, the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.
CONCLUSION
Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway. These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
Core Tip: The present work showed that inhibition of metabotropic glutamate receptor 5 can activate the AMPK signaling pathway, promoting the entry of transcription factor EB into the nucleus and enhancing autophagy, which will ameliorate hepatocyte steatosis.
