Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6

Ran Li; Zhengqin Ye; Dunmin She; Ping Fang; Guannan Zong; Kerong Hu; Dehong Kong; Wei Xu; Ling Li; Yun Zhou; Keqin Zhang; Ying Xue

doi:10.2147/DDDT.S384884

Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6

Drug Des Devel Ther. 2022 Oct 12:16:3557-3572. doi: 10.2147/DDDT.S384884. eCollection 2022.

Authors

Ran Li¹, Zhengqin Ye¹, Dunmin She^{2

3}, Ping Fang¹, Guannan Zong¹, Kerong Hu¹, Dehong Kong¹, Wei Xu¹, Ling Li¹, Yun Zhou¹, Keqin Zhang¹, Ying Xue¹

Affiliations

¹ Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
² Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China.
³ Department of Endocrinology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, People's Republic of China.

Abstract

Objective: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms.

Methods: Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6.

Results: Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R.

Conclusion: Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.

Keywords: Semaglutide; microRNA-5120; non-alcoholic fatty liver disease; type 2 diabetes mellitus; α/β hydrolase domain-6.

MeSH terms

Animals
Diabetes Mellitus, Type 2* / metabolism
Glucagon-Like Peptides
Liver / metabolism
Mice
Mice, Inbred C57BL
MicroRNAs* / genetics
MicroRNAs* / metabolism
Monoacylglycerol Lipases / metabolism
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

MicroRNAs
semaglutide
Glucagon-Like Peptides
ABHD6 protein, mouse
Monoacylglycerol Lipases

Grants and funding

This study was sponsored by the National Natural Science Foundation of China (Grant No. 82270877, 81974105), Cultivation project for National Natural Science Foundation of Shanghai Tongji Hospital.