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  • At the mechanistic level our results strongly suggested that

    2019-05-16

    At the mechanistic level, our results strongly suggested that the cholestatic protective effect of STS was most likely accounted for by the activation of LXR, a nuclear receptor known for its anti-cholestatic activity. The activation of LXR was supported by the induction of typical LXR target genes, such as Lxrα and Abcg5, in the liver of STS mice. The suppression of the ileal bms-690514 of Asbt in the LCA-treated STS mice (Fig. 4C) was also consistent with that observed in the LCA-treated FABP-VP-LXRα transgenic mice, in which the expression of the constitutively activated LXRα (VP-LXRα) was expressed in the liver and intestine under the control of the FABP gene promoter. Since the STS transgene is expressed in both the liver and small intestine, it is likely that its expression in both tissues contributed to the protective phenotypes. The activation of LXR in STS mice was consistent with the notion that STS plays an important role in the control of the homeostasis of oxysterol-derived endogenous LXR ligands. Specifically, the cholesterol derivative oxysterols are endogenous LXR agonists. Oxysterols have been reported to directly bind to the LXR ligand binding domain, recruit coactivators to LXR, and activate LXR signaling in several in vitro and in vivo studies. Oxysterols can be sulfonated by the cholesterol sulfotransferase SULT2B1b and the resultant sulfated oxysterols antagonize the LXR activity. The sulfation of oxysterols is reversible and the desulfation is catalyzed by STS. Indeed, patients with STS deficiency showed increased serum levels of cholesterol sulfates and oxysterol sulfates. Therefore, STS may function to enhance LXR agonist availability and reduce LXR antagonist levels, leading to the net gain of increased LXR activation. This notion was supported by our experimental results showing that transfection of STS and SULT2B1b increased and decreased the 22-HC induced activation of LXR in the reporter gene assay, respectively (Fig. 5C). Interestingly and surprisingly, the activation of LXR signaling pathways in STS mice was gene- selective. For example, the LXR responsive and Srebp-1c mediated lipogenic pathway was not activated and the STS mice did not exhibit spontaneous steatosis. Additionally, Cyp7a1, a prototypic LXR target gene, was not induced in the STS mice. Although the mechanism for this gene selectivity remains to be understood, the potential therapeutic outcome of this selectivity is favorable. Although LXR has been suggested to be a promising therapeutic target for cholestasis, several existing synthetic LXR agonists such as T0901317 and GW3965 not only regulate bile acid homeostasis, but also promote lipogenesis by activating lipogenic genes, thus limiting their therapeutic applicability. By contrast, the natural LXR agonist oxysterols, such as 25-hydroxycholesterol and 22-hydroxycholesterol, showed selective modulation of the LXR target gene Abca1, which is a cholesterol transporter responsible for cholesterol elimination. LXR signaling has also been shown to regulate inflammation and fibrosis within the liver. We cannot exclude the possibility that the anti-inflammatory and anti-fibrotic activities of LXR may have also contributed to the protective effect of STS. Indeed, we have previously reported that the expression of pro-inflammatory genes was reduced in STS transgenic mice fed a high-fat diet or in ob/ob mice that express the STS transgene. In the current study, we used an acute model of cholestasis. We plan to analyze the effects of STS on inflammation and fibrosis in chronic cholestatic models in our future studies.
    Conflict of interest
    Author’s contributions
    Acknowledgments This work was supported in part by the National Institutes of Health grants DK083952 and HD073070 (to W.X.). W.X. is also supported bms-690514 in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy.