P25-09 The role of Constitutive Androstane Receptor (CAR) in PFOA-induced hepatic steatosis

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) has become the most common cause of chronic liver disease worldwide This condition represents a major health concern as the leading cause of liver transplantation in the United States [2] . Exposure to xenobiotics, known as environmental obesogens, has emerged as a potential contributing factor to Toxicant-Associated Fatty Liver Disease (TAFLD) [3] . Perfluorooctanoic acid (PFOA), a member of the per- and polyfluoroalkyl substances (PFAS) group, has widespread industrial applications and can enter the food chain through bioaccumulation or food packaging transfer. PFOA induces hepatotoxicity and hepatic steatosis, an effect mediated by nuclear receptor [4] . Among them, the Constitutive Androstane Receptor (CAR) plays a key role at the crossroads between xenobiotic detoxification and energy metabolism regulation, making it an interesting target for understanding the steatogenic effect of PFOA. This study focuses on the involvement of CAR in PFOA-induced steatosis. Using WT and CAR knockout (CAR-/-) mice, the study demonstrates that acute PFOA exposure leads to CAR activation in WT mice. PFOA induces hepatomegaly in both WT and CAR-/- mice, though the effect is less pronounced in CAR-/- mice. Additionally, PFOA increases lipid uptake by activating the expression of the fatty acid transporter CD36 and induces hepatic steatosis in both WT and CAR-/- mice. However, in absence of CAR, smaller lipid droplets are observed. Ongoing studies aim to investigate the proteomics of lipid droplets induced by PFOA exposure in WT and CAR-/- mice to further elucidate the role of CAR in their formation.