Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydrox-ysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis. Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxy-sterol sulfates to the agonistic oxysterols. Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endog-enous LXR ligands.