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

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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.

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Abbreviations

ALD:

Alcoholic liver disease.

AMPK:

AMP-activated protein kinase.

ACC:

Acetyl-CoA.

LKB1:

Liver kinase B1.

CaMKK2:

Ca2+/Calmodulin-dependent protein kinase kinase2.

T2D:

Type 2 diabetes.

NAFLD:

Nonalcoholic fatty liver disease.

AST:

Aspartate aminotransferase.

ALT:

Alanine aminotransferase.

TC:

Total cholesterol.

TG:

Triglycerides.

SREBP-1c:

Sterol regulatory element-binding protein 1c.

PPAR-α:

Peroxisome proliferator-activated receptorα.

SCD1:

stearyl-coenzyme A desaturase 1.

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Acknowledgements

Not applicable.

Funding

This study were supported by National Natural Science Foundation of China (No. 81900535) and Natural Science Foundation of Fujian Province (No. 2021J05038).

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Authors and Affiliations

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

    Fotian Xie, Dongmei Wang, Kwok Fai So, Jia Xiao & Yi Lv

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

    Yuanming Zhong

  3. Institute of Clinical Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China

    Jia Xiao

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  1. Fotian Xie
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Contributions

FX and YZ conducted the experiments, YL and DW drafted this article. DW, JX and KS helped to revise the manuscript. JX and YL participated in its design and coordination. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yi Lv.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of Fujian Normal University. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fujian Normal University (Approval No, IACUC-20190020).

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The manuscript has been submitted to the preprint at the Research Square, and this work was licensed under a CC BY 4.0 License (DOI: https://doi.org/10.21203/rs.3.rs-800909/v1).

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The authors declare that they have no competing interests.

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Xie, F., Zhong, Y., Wang, D. et al. Metformin protects against ethanol-induced liver triglyceride accumulation by the LKB1/AMPK/ACC pathway. Mol Biol Rep 49, 7837–7848 (2022). https://doi.org/10.1007/s11033-022-07610-y

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  • DOI: https://doi.org/10.1007/s11033-022-07610-y

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