The role of GPER-mediated AMPKα signal in the prevention effect of (-)-epicatechin on metabolic dysfunction-associated steatohepatitis.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases worldwide. Effective drugs and early diagnostic tools remain lacking, underscoring the urgent need for improved preventive measures, such as dietary interventions. (-)-Epicatechin (EC), a naturally polyphenolic compound that exists in tea, chocolate, and various fruits, has high bioavailability and exhibits evident lipid-lowering, antioxidant, and anti-inflammatory properties. Although the beneficial regulation effect of EC on metabolism disorders has been reported, the effects and specific molecular mechanisms by which EC mitigates the occurrences of MASH remain unclear. The present study demonstrated that incorporating EC into the diet prevented the onset and progression of MASH, which presented as the alleviation effects of EC treatment on the high-fat/high-cholesterol diet-induced liver damage, steatosis, apoptosis, oxidative stress, inflammation, and fibrosis in mice. In vitro, we also found that EC treatment effectively mitigated lipid accumulation and oxidative stress in palmitic acid-challenged hepatocytes. Mechanistically, the present study novelty certified that EC mainly up-regulates the G protein-coupled estrogen receptor (GPER) expression, a non-classical steroid receptor, mediating the activation of AMP-activated protein kinase alpha (AMPKα) signaling pathway, thereby mitigating the occurrences and progression of MASH. In summary, EC prevents the occurrences of MASH via activating the GPER-mediated AMPKα signaling pathway, which provides a substantial theoretical foundation and prompts the potential application value for EC as a candidate nutritional regulator in preventing metabolic-related diseases.