W. Li, Bowen Fan, Hongxia Li, Qiong Du, Jiaheng Lin, Yi Yang, Xiaolin Ding, Haoran Zhang, Haibo Xia, Binafsha Manzoor Syed, C. Yan Cheng, Qizhan Liu
Arsenic in groundwater and agricultural systems poses a challenge to food safety and public health. Although environmental arsenic exposure is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), its molecular mechanism remains unclear. Chronic arsenic exposure induced hepatic steatosis and upregulated fatty acid synthase (FASN) in mice. Mechanistically, arsenic triggered splicing of X-box binding protein 1 (XBP1) into its active form, XBP1s, which promoted the transcription of glutamine-fructose-6-phosphate aminotransferase 1 (GFPT1). This increased flux of the hexosamine biosynthetic pathway (HBP) elevated UDP-GlcNAc and O-GlcNAcylation. Mass spectrometry identified Ser509 as an O-GlcNAcylated site on FASN, and its mutation abolished arsenic-induced lipid accumulation. O-GlcNAcylation at Ser509 stabilized FASN by inhibiting ubiquitin-mediated degradation and promoting fatty acid synthesis. This study identifies the XBP1s-GFPT1 axis and O-GlcNAcylation of FASN S509 as essential in arsenic-induced MASLD.