Phytochemical gallic acid alleviates nonalcoholic fatty liver disease via AMPK-ACC-PPARa axis through dual regulation of lipid metabolism and mitochondrial function

Jan 7, 2023Phytomedicine : international journal of phytotherapy and phytopharmacology

Plant compound gallic acid may reduce fatty liver disease by improving fat metabolism and energy production

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Abstract

Gallic acid (GA) significantly activates the AMPK-ACC-PPARα axis, which is associated with protection against nonalcoholic fatty liver disease (NAFLD) progression.

A close link was found between the activation of the AMPK-ACC-PPARα axis and the progression of NAFLD in human fatty liver.
GA was shown to pharmacologically activate AMPK, leading to reprogrammed lipid metabolism and improved mitochondrial function in fatty liver models.
Activation of AMPK provided substantial protection against NASH and fibrosis in mice with high-fat diet-induced NAFLD.
Silencing AMPK exacerbated lipid deposition in hepatocytes and promoted the progression of NASH and NAFLD-associated liver cancer.
GA was found to directly interact with AMPKα, inactivating the ACC-PPARα signaling pathway and repairing liver damage.

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BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) usually includes NAFL called simple hepatosteatosis and nonalcoholic steatohepatitis (NASH) called more steatohepatitis. The latter is a leading pathogenic promotor of hepatocellular carcinoma (HCC). Phytochemical gallic acid (GA) has been proved to exert positive efficacy in HCC in our work, but it remains unclear whether its hepatoprotective effect attributes to the controlled transition from simple steatosis to steatohepatitis.

PURPOSE: This work aims to provide mechanistic evidence that the therapeutic application of GA in NAFLD is indispensable for GA-meliorated NASH progression.

METHODS: The high-fat diet (HFD)-fed mice and palmitic acid (PA) and oleic acid (OA)-treated hepatocytes were used collectively in this study. Bioinformatic analysis, clinical subjects, RNA-Seq, molecular docking, and confirmatory experiments were performed comprehensively to uncover the pathological link between the AMPK-ACC-PPARα axis and the treatment of NAFLD.

RESULTS: By analyzing the clinical subjects and GEO database, we find a close link between the activation of AMPK-ACC-PPARα axis and the progression of NAFLD in human fatty liver. Subsequent assays show that GA exhibits pharmacological activation of AMPK, reprogramming lipid metabolism, and reversing mitochondrial function in cellular and murine fatty liver models. AMPK activation conferred substantial protection against murine NASH and fibrosis in the context of HFD-induced NAFLD. In contrast, silencing AMPK badly aggravates lipid deposition in hepatocytes, boosting NASH and NAFLD-associated HCC progression. The in silico docking, in vitro surface plasmon resonance and in vivo cellular thermal shift assay collectively reveal that GA directly interacts with AMPKα, which inactivates the ACC-PPARα axis signaling. Notably, GA repairs the liver damage, lipotoxicity, and mitochondrial respiratory capacity caused by excessive mtROS, while showing minimal effects in other major organs in mice.

CONCLUSION: Our work identifies GA as an important suppressor of NAFLD-HCC progression, and underscores the AMPK-ACC-PPARα signal axis as a potential therapeutic target for NAFLD treatment.

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Phytochemical gallic acid alleviates nonalcoholic fatty liver disease via AMPK-ACC-PPARa axis through dual regulation of lipid metabolism and mitochondrial function

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