Ganoderic Acid A Alleviates NAFLD by Facilitating PPARα-CPT1A Complex and Enhancing Gut Microbiota Diversity

Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health crisis, characterized by impaired fatty acid oxidation and lipid accumulation. Ganoderic acid A (GAA), a traditional Chinese medicine, has been reported to have significant anticancer and anti-senescence effects. However, the role and molecular mechanisms of GAA in NAFLD are unclear. Here, we found GAA significantly alleviated obesity and metabolic disorders induced by high-fat diet (HFD), reducing body weight, fat mass, and serum lipid levels while improving insulin sensitivity. Importantly, GAA treatment resulted in decreased hepatic lipid accumulation, inflammation, and fibrosis, alongside upregulation of key fatty acid oxidation (FAO) genes. Mechanistically, GAA enhances the expression and activity of peroxisome proliferator-activated receptor alpha (PPARα), thereby promoting the expression of FAO genes and improving hepatic lipid metabolism. Additionally, GAA promoted the interaction between PPARα and carnitine palmitoyltransferase 1a (CPT1a), further enhancing the transcriptional activation of FAO genes. Notably, GAA modulated the gut-liver axis by restoring microbial diversity, enriching beneficial microbiota, and increasing short-chain fatty acids (SCFAs) levels. These findings underscore the dual-action efficacy of GAA against NAFLD, involving both hepatic PPARα activation and gut microbiota modulation, positioning GAA as a promising functional food ingredient for health management.