br Conclusions and future perspectives br Conflict of intere

Conclusions and future perspectives
Conflict of interest
Author’s contributions
Introduction Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two opposing mechanisms involved in regulating the chemical and functional homeostasis of endogenous and exogenous chemicals. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids and is expressed in many tissues including the liver, where the circulating steroids are extensively metabolized. By altering the levels of sulfated versus non-sulfated steroids, STS is important in the regulation of the cellular actions of steroid hormones. Bile acids are the major catabolic end products of cholesterol in the liver. As a major constituent in the bile, bile acids play an important physiological role in the solubilization and d-glucose of lipids and other lipophilic nutrients. Bile acids also function in signaling by activating receptors such as the farnesoid X receptor (FXR) and G protein-coupled receptor 5 (TGR5, also known as G protein-coupled bile acid receptor 1, or GPBAR1). In addition to their beneficial functions, excessive bile acids are potentially toxic when they accumulate in the body. For example, LCA, a secondary bile acid, is a potent cholestatic agent and can induce liver injury and other pathological changes when it is not efficiently eliminated. The nuclear receptor liver X receptor (LXR) represents a promising therapeutic target for bile acid detoxification by enhancing the metabolism and elimination of bile acids as well as by reducing inflammation. Both pharmacological stimulation and genetic activation of LXR prevented LCA-induced hepatotoxicity. In contrast, LXRα and β double knockout mice were more sensitive to bile acid toxicity. However, several existing synthetic LXR agonists not only regulate bile acid homeostasis, but also promote lipogenesis and are pro-atherogenic. By contrast, oxysterols, natural LXR agonists, showed selective modulation of LXR target genes that are responsible for cholesterol elimination, while not over-activating lipogenic genes. STS plays a key role in regulating the homeostasis of endogenous ligands for LXR. Oxysterols, oxygenated cholesterol derivatives, are endogenous ligands of LXR. Like many other cholesterol derivatives, oxysterols can be sulfated by sulfotransferases such as the cholesterol sulfotransferase SULT2B1b, and the sulfonated forms of oxysterols can antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. Knowing that LXR has anti-cholestasis activity, we hypothesize that STS may attenuate cholestasis by activating LXR through increased availability of endogenous LXR agonists and reducing the level of endogenous LXR antagonists. In this report, we show that transgenic over-expression of STS in the liver and small intestine enhanced bile acid elimination and attenuated LCA-induced liver damage in mice. The protective effect of STS was associated with the induction of LXR target genes. Our results suggest a novel function of STS in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.
Methods
Results
Discussion In this study, we uncovered a novel function of STS in the protection of LCA-induced cholestasis and liver toxicity. The cholestatic protective effect of the STS transgene was associated with reduced hepatic bile acid content and increased fecal output of bile acids. The reduction in the hepatic bile acid may have resulted from the combined effect of the increased expression of canalicular bile acid efflux transporter Mrp2 and increased expression of cholesterol efflux transporter Abcg5. Mutation of the MRP2 gene results in Dubin–Johnson syndrome and presents with cholestasis in some neonates. The increased fecal output of bile acids may be explained by the suppression of ileal Asbt, a key intestinal bile acid uptake transporter responsible for the enterohepatic recirculation of bile acids. Genetic deletion of Asbt disrupted enterohepatic circulation and resulted in bile acid malabsorption in mice.