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

Abstract

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 NaAsO 2 -induced hepatic lipid metabolism disorder in mice and AML12 cells. We observed that chronic exposure to NaAsO 2 induced hepatic inflammation, glucose intolerance and lipid deposition, accompanied by impairing liver function, and increasing TC and TG levels in serum and liver. Mechanistically, NaAsO 2 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 NaAsO 2 exposure-induced lipid metabolism disorder by regulating the FXR/SREBP1 signaling pathway in AML12 cells. Collectively, this study revealed that chronic NaAsO 2 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.