Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China.
Drug Des Devel Ther. 2022 Oct 12;16:3557-3572. doi: 10.2147/DDDT.S384884. eCollection 2022.
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.
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.
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.
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.
虽然非酒精性脂肪性肝病（NAFLD）的发病机制已经得到了广泛的研究，但它的潜在发病机制仍不清楚，目前也没有针对 NAFLD 的批准的治疗策略。本研究的目的是观察司美格鲁肽对体内和体外 NAFLD 的有益作用及其潜在的分子机制。
用司美格鲁肽治疗 12 周的 2 型糖尿病（T2DM）合并 NAFLD 小鼠。通过肝功能、血脂、肝脂、H&E 染色、油红染色和 Sirius 染色评估肝脏功能和结构。通过体内和体外的 qPCR 和 Western blot 测量α/β水解酶结构域-6（ABHD6）的表达。然后，进行双荧光素酶报告基因实验验证上游 miR-5120 对 ABHD6 的调控作用。
我们的数据显示，司美格鲁肽给药可显著改善 T2DM 合并 NAFLD 小鼠的肝功能和肝脂肪变性。此外，与对照组相比，T2DM+NAFLD 小鼠肝脏中 ABHD6 上调，miR-5120 下调，HG+FFA 刺激的 Hepa 1-6 肝细胞也是如此。有趣的是，在司美格鲁肽干预后，T2DM+NAFLD 小鼠肝脏和 HG+FFA 刺激的 Hepa 1-6 肝细胞中 ABHD6 的表达明显降低，而 miR-5120 的表达增加。我们还发现，miR-5120 可以调节肝细胞中 ABHD6 的表达，而司美格鲁肽可以通过 miR-5120 调节 ABHD6 的表达。此外，GLP-1R 在小鼠肝组织和 Hepa 1-6 细胞中广泛表达。司美格鲁肽可以通过 GLP-1R 调节 miR-5120/ABHD6 的表达。
我们的数据揭示了司美格鲁肽改善 T2DM+NAFLD 患者肝脂肪变性的潜在机制，并为 miR-5120/ABHD6 在 T2DM+NAFLD 发病机制中的病理作用提供了新的见解。
