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A novel combination of metformin and resveratrol alleviates hepatic steatosis by activating autophagy through the cAMP/AMPK/SIRT1 signaling pathway

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that is associated with the accumulation of triglycerides (TG) in hepatocytes. Resveratrol (RSV), as a natural product, and metformin have been reported to have potential lipid-lowering effects for the treatment of NAFLD via autophagy, but the combined effects of both have not yet been studied. The current study aimed to investigate the role of autophagy in the lipid-lowering effects of RSV, alone and in combination with metformin, on the hepatic steatosis model of HepG2 cells and elucidate the mechanism of action. Triglyceride measurement and real-time PCR showed that RSV-metformin reduced lipid accumulation and the expression of lipogenic genes in palmitic acid (PA)-induced HepG2 cells. Additionally, the LDH release assay indicated that this combination protected HepG2 cells against PA-induced cell death through autophagy. The western blotting analysis revealed that RSV-metformin induced autophagy by reducing the expression of p62 and increasing LC3-I and LC3-II proteins. This combination also enhanced cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels in HepG2 cells. Furthermore, SIRT1 inhibitor treatment inhibited autophagy induced by RSV-metformin, which indicated the autophagy induction is SIRT1-dependent. This study demonstrated for the first time that RSV-metformin reduced hepatic steatosis by triggering autophagy via the cAMP/AMPK/SIRT1 signaling pathway.

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Data availability

The datasets analyzed during this study are available from the corresponding author by reasonable request.

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The study was funded by Shahid Beheshti University of Medical Sciences.

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  1. Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Havva Afshari & Shokoofe Noori

  2. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Afshin Zarghi

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Havva Afshari: wrote the manuscript and interpreted the results. Shokoofe Noori: supervised and designed the study and analyzed the data. Afshin Zarghi: contributed to the conduction of the experiments. The authors declare that all data were generated in-house and that no paper mill was used.

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Afshari, H., Noori, S. & Zarghi, A. A novel combination of metformin and resveratrol alleviates hepatic steatosis by activating autophagy through the cAMP/AMPK/SIRT1 signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3135–3148 (2023). https://doi.org/10.1007/s00210-023-02520-7

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