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

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-PPAR alpha 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-PPAR alpha 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 in-teracts with AMPK alpha, which inactivates the ACC-PPAR alpha 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-PPAR alpha signal axis as a potential therapeutic target for NAFLD treatment.

Automated summary

This study finds that the phytochemical gallic acid (GA) has a positive effect in the treatment of nonalcoholic fatty liver disease (NAFLD), exerting hepatoprotective effects by controlling the transition from simple hepatosteatosis to steatohepatitis.