Ellagitannins-Derived Intestinal Microbial Metabolite Urolithin A Ameliorates Fructose-Driven Hepatosteatosis by Suppressing Hepatic Lipid Metabolic Reprogramming and Inducing Lipophagy

Excessive fructose consumption exacerbates the progression of nonalcoholic fatty liver disease (NAFLD) by disrupting hepatic lipid homeostasis. This study sought to evaluate the efficacy of urolithin A (UroA) in a fructose-induced NAFLD mouse model. UroA was administered in the high-fructose-fed mice to investigate the antisteatotic effects in vivo. Fructose-stimulated HepG2 cells and primary hepatocytes were established for in vitro mechanistic assessment. The results suggested that UroA ameliorated fructose-induced hepatic steatosis in mice. Mechanistically, UroA impaired lipogenesis and enhanced β-oxidation in the livers of fructose-fed mice. Notably, UroA facilitated hepatic lipophagy through the AMPK/ULK1 pathway both in vivo and in vitro, degrading lipid droplets for fueling β-oxidation. This study indicates that UroA alleviates excessive lipid accumulation and restores lipid homeostasis in the livers of fructose-fed mice by suppressing lipid metabolic reprogramming and triggering lipophagy. Therefore, dietary supplementation of UroA or ellagitannins-rich foods may be beneficial for NAFLD individuals with high fructose intake.

fructose; lipogenesis; lipophagy; nonalcoholic fatty liver disease; urolithin A.