Nobiletin mitigates NAFLD via lipophagy and inflammation

Nonalcoholic fatty liver disease (NAFLD), an increasingly serious health issue around the world, is characterized as a lipid metabolic disorder without any satisfactory treatment. Nobiletin (NOB), a citrus flavonoid, is considered a promising candidate for NAFLD prevention although there is limited research towards its exact mechanism. In this study, the preventative effect of NOB on NAFLD was investigated using high fat diet-fed ApoE^-/- mice and free fatty acid-treated HepG2 cells. The results of hematoxylin and eosin staining of liver sections revealed that L-NOB (50 mg kg^-1 d^-1 NOB), M-NOB (100 mg kg^-1 d^-1 NOB) and H-NOB (200 mg kg^-1 d^-1 NOB) could significantly ameliorate NAFLD. Further exploration illustrated that NOB alleviated hepatic steatosis mainly via TFEB-mediated lysosomal biogenesis and lipophagy. Besides, NOB could mitigate NLRP3 inflammasome assembly and modulate M1/M2 macrophage polarization in vivo and in vitro. The mechanisms above allowed NOB to attenuate NAFLD, but their close association needed further investigation. Our research not only illustrated NOB as a potential candidate for NAFLD prevention, but also provided new insight into the pathogenic mechanisms of NAFLD development.