1,25(OH)2 D3 attenuates hepatic steatosis by inducing autophagy in mice.

Objective 1,25(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. Methods Male C57BL/6 mice fed a high-fat diet (HFD) were injected with 1,25(OH)2D3 for 4 weeks. These mice were given 3-methyladenine (3-MA) to inhibit autophagy. HepG2 cells were preincubated 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. Results 1,25(OH)2D3 diminished HFD-induced liver damage and steatosis, changes accompanied by autophagy and ATG16L1 expression upregulation. Inhibition of 1,25(OH)2D3-induced autophagy mediated by 3-MA 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. The protective effects of 1,25(OH)2D3-mediated autophagy against lipid accumulation were abolished by 3-MA. Furthermore, siRNA-mediated ATG16L1 knockdown prevented 1,25(OH)2D3-induced autophagy, resulting in increased fat accumulation. Conclusions The data suggest that 1,25(OH)2D3 may ameliorate hepatic steatosis by inducing autophagy by upregulating ATG16L1.