Exercise attenuates hepatic lipid accumulation via VDR/AMPK-mediated autophagy activation in vitamin D-deficient mice

Vitamin D deficiency (VDD) is a global health issue associated with hepatic lipid accumulation. Although exercise serves as an effective non-pharmacological intervention for metabolic disorders, its molecular mechanisms remain unclear. This study aimed to investigate the underlying mechanisms by which exercise attenuates VDD-induced hepatic lipid accumulation. We established a VDD mouse model and applied exercise as an intervention for 12 weeks. To confirm whether AMPK-induced autophagy is mediated by vitamin D receptor (VDR), we knocked down VDR in AML12 cells using lentivirus-mediated VDR shRNA and activated AMPK in stably VDR knockdown cells using the AMPK activator GSK621. In vivo studies revealed that exercise alleviated VDD-induced hepatic lipid accumulation by upregulating hepatic VDR and activating AMPK-mediated autophagy. In vitro studies showed that VDR knockdown suppressed autophagy and inhibited AMPK phosphorylation in AML12 cells. AMPK activator GSK621 treatment reversed these processes. In conclusion, exercise effectively attenuates VDD-induced hepatic lipid accumulation via VDR/AMPK-mediated autophagy activation.