Store-Operated Calcium Channel and Inositol Triphosphate Receptor Calcium Channel Hyperactivation Inhibits Hepatocyte Autophagy to Promote Nonalcoholic Fatty Liver Disease

Previously, we demonstrated that store-operated calcium channel (SOCC) and inositol triphosphate receptor (IP3R) calcium channel upregulation inhibits autophagy via (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways to promote nonalcoholic fatty liver disease (NAFLD) in vitro; however, it remains unclear whether this mechanism exists in vivo. In this study, We observed that Lee’s Index, body mass index, plasma lipid indices, and hepatic triglyceride and total cholesterol content were increased in high-fat diet(HFD)-fed mice compared to normal diet(ND)-fed mice, whereas hepatocytes from HFD-fed mice showed macrovesicular steatosis and hepatocellular ballooning. The levels of SOCC and IP3R channel proteins such as calcium release-activated calcium channel protein 1, stromal interaction molecule 1, transient receptor potential canonical 1 (TRPC1) and IP3R were markedly increased in hepatocytes from HFD-fed mice compared to those from ND-fed mice, suggesting calcium channels over-activation. The levels of key proteins such as extracellular regulated protein kinases 1/2 (ERK1/2), phosphorylated(p)-forkhead/winged helix O 3 (FOXO3), p-tuberous sclerosis 2, p-ribosomal protein S6, and p-Unc-51 like autophagy activating kinase 1 in (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways were increased in HFD-fed mice, whereas autophagy-related gene 12 (ATG12) expression was downregulated, indicating FOXO signaling inhibition and mTORC1 signaling activation. Furthermore, the levels of autophagy-related proteins such as microtubule-associated protein 1-light chain 3 B and Yeast ATG 6 homolog were decreased in HFD-fed mice, suggesting autophagy inhibition. Importantly calcium channel blockers (CCBs) reversed HFD-induced abnormal changes in mice fed with HFD + CCB. Taken together, these results indicated that SOCC and IP3R upregulation and subsequent increased cytoplasmic calcium signaling inhibit hepatocyte autophagy via (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling, thus leading to lipid droplet accumulation and NAFLD in vivo.