Chronic arsenic exposure induces hepatic lipid metabolism disorder by regulating the FXR/SREBP1 signaling pathway.

Arsenic is a widespread environmental metalloid contaminant that primarily targets the liver, inducing hepatic injury and metabolic disturbance. However, the precise mechanisms underlying chronic arsenic exposure-induced hepatic lipid dysregulation have not been fully elucidated. Here, we investigated the molecular mechanisms of NaAsO2-induced hepatic lipid metabolism disorder in mice and AML12 cells. We observed that chronic exposure to NaAsO2 induced hepatic inflammation, glucose intolerance and lipid deposition, accompanied by impairing liver function, and increasing TC and TG levels in serum and liver. Mechanistically, NaAsO2 exposure regulated the FXR/SREBP1 signaling pathway by reducing FXR and SHP expression, and upregulating the expression of lipogenic genes including SREBP1, FASN and PPARγ in mice and AML12 cells. Meanwhile, FXR activator GW4064 pretreatment could alleviate NaAsO2 exposure-induced lipid metabolism disorder by regulating the FXR/SREBP1 signaling pathway in AML12 cells. Collectively, this study revealed that chronic NaAsO2 exposure caused hepatic lipid metabolism disorder by regulating the FXR/SREBP1 signaling pathway. These findings establish a mechanistic foundation for the management of arsenic-induced liver diseases.