Chlorogenic Acid Modulates Autophagy by Inhibiting the Activity of ALKBH5 Demethylase, Thereby Ameliorating Hepatic Steatosis

Chlorogenic acid (CGA) is a naturally occurring plant component with the purpose of alleviating hepatic lipid deposition biological activities. However, the molecular mechanism behind this ability of CGA remains unelucidated. Consequently, we investigated the effect of CGA on hepatic lipid accumulation and elucidated its underlying mechanism. Our study used a high-fat diet (HFD)-induced mouse nonalcoholic fatty liver disease (NAFLD) model in mice to investigate the impact of CGA on hepatic lipid accumulation. The results revealed that the oral administration of CGA can ameliorate HFD-induced hepatic lipid deposition, reduce the NAFLD activity score (NAS), enhance liver autophagy, mitigate liver cell structural damage, and inhibit the MAPK/ERK signaling pathway. Meanwhile, CGA treatment increased the LC3B:LC3B ratio and decreased P62 expression. Cell experiments demonstrated that autophagy contributes to the ability of CGA to alleviate lipid deposition. Further analysis revealed that CGA specifically binds to ALKBH5 and inhibits its m(6)A methylase activity. The inhibition of ALKBH5 activity significantly reduces AXL mRNA stability in liver cells. The AXL downregulation resulted in suppressing ERK signaling pathway activation. Overall, this study demonstrates that CGA can alleviate hepatic steatosis by regulating autophagy through the inhibition of ALKBH5 activity inhibition.