二甲双胍通过 LKB1/AMPK/ACC 通路防止乙醇诱导的肝甘油三酯积聚。

Metformin protects against ethanol-induced liver triglyceride accumulation by the LKB1/AMPK/ACC pathway.

机构信息

Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, College of Life Sciences, Fujian Normal University, Fuzhou, China.

School of Physical Education and Sport Science, Fujian normal university, Fuzhou, China.

出版信息

Mol Biol Rep. 2022 Aug;49(8):7837-7848. doi: 10.1007/s11033-022-07610-y. Epub 2022 Jun 22.

DOI:10.1007/s11033-022-07610-y

PMID:35733070

Abstract

BACKGROUND

Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease (ALD). Metformin serves as an AMPK activator and has been shown to have lipids lowering effects in non-alcoholic fatty liver disease (NAFLD), but its role in ALD remains unclear. The purpose of this study was to explore the potential mechanism of metformin regulating lipid metabolism in ALD.

METHODS AND RESULTS

In vitro and in vivo ALD models were established using AML12 cells and C57BL/6 mice, respectively. To determine the effect of metformin on ALD in vitro, the concentration of cellular triglyceride was examined by Nile red staining and a biochemical kit. To further reveal the role of metformin on ALD in vivo, liver tissues were examined by HE and oil red O staining, and the levels of ALT and AST in serum were determined via an automatic biochemical analyzer. The expression of mRNA and proteins were measured using qRT-PCR and Western blot, respectively. The role of the LKB1/AMPK/ACC axis on metformin regulating ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference. The results showed metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK, inhibiting ACC, reducing SREBP1c, and increasing PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver triglyceride accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo.

CONCLUSION

Metformin protects against lipid formation in ALD by activating the LKB1/AMPK/ACC axis.

摘要

背景

肝脂质积累是酒精性肝病 (ALD) 的主要病理特征之一。二甲双胍作为 AMPK 激活剂，已被证明在非酒精性脂肪性肝病 (NAFLD) 中有降低血脂的作用，但在 ALD 中的作用尚不清楚。本研究旨在探讨二甲双胍调节 ALD 脂质代谢的潜在机制。

方法和结果

分别使用 AML12 细胞和 C57BL/6 小鼠建立体外和体内 ALD 模型。为了确定二甲双胍对体外 ALD 的影响，通过尼罗红染色和生化试剂盒检测细胞内甘油三酯的浓度。为了进一步揭示二甲双胍在体内对 ALD 的作用，通过 HE 和油红 O 染色检查肝组织，并通过自动生化分析仪测定血清中 ALT 和 AST 的水平。使用 qRT-PCR 和 Western blot 分别测量 mRNA 和蛋白质的表达。通过 siRNA 和 AAV-shRNA 干扰评估 LKB1/AMPK/ACC 轴在二甲双胍调节乙醇诱导的脂质积累中的作用。结果表明，二甲双胍通过激活 AMPK、抑制 ACC、降低 SREBP1c 和增加 PPARα 来减少 AML12 细胞中乙醇诱导的脂质积累。此外，与对照组小鼠相比，二甲双胍治疗抑制了乙醇诱导的肝甘油三酯积累以及血清中 ALT 和 AST 的增加。干扰 LKB1 减弱了二甲双胍在体外和体内对乙醇诱导的脂质积累的作用。