1,25?OH?₂D₃ Attenuates Hepatic Steatosis By Inducing Autophagy In Mice

Aim1,25?OH?₂D₃ has been reported to attenuate liver steatosis;however,its exact mechanism of action remains poorly understood.This study aimed to determine whether 1,25?OH?₂D₃ can attenuate hepatic steatosis by inducing autophagy.MethodsMale C57BL/6 mice fed a high-fat diet?HFD?were injected with 1,25?OH?₂D₃ for 4 weeks.3-methyladenine?3-MA?was given to these mice to inhibit autophagy.HepG2 cells were pre-incubated with a free fatty acid?FFA?and then treated with 1,25?OH?₂D₃.Vitamin D receptor?VDR?shRNA and autophagy-related 16-like 1?ATG16L1?siRNA were used for VDR knockdown or ATG16L1 silencing,respectively.Results1,25?OH?₂D₃ diminished HFD-induced liver damage and steatosis,changes accompanied by autophagy and ATG16L1 expression upregulation.3-MA-mediated inhibition of 1,25?OH?₂D₃-induced autophagy blocked the protective effects of 1,25?OH?₂D₃ on hepatic steatosis.Additionally,1,25?OH?₂D₃-induced autophagy appeared to play a role in anti-inflammation and lipid metabolism modulation in the liver.In HepG2 cells,1,25?OH?₂D₃ reduced lipid accumulation and increased autophagy and ATG16L1 expression;however,this effect was abrogated after VDR knockdown.3-MA abolished the protective effects of I,25?OH?2D3-mediated autophagy against lipid accumulation.Furthermore,siRNA-mediated ATG16L1 knockdown prevented 1,25?OH?₂D₃-induced autophagy,resulting in increased fat accumulation.ConclusionThe data suggest that 1,25?OH?₂D₃ may ameliorate hepatic steatosis by inducing autophagy by upregulating ATG16L1.