title: Schisandrol B protects against cholestatic liver injury through pregnane X receptors.
abstract: Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera.
  
  
  
  Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB.
  
  
  
  SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent.
  
  
  
  These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Dongshun
authors.initials: D
authors.lastname: Li
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000139:chemically induced / Q000517:prevention & control*; D034242:Cyclooctanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D017705:Lignans / Q000494:pharmacology*; D008095:Lithocholic Acid; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C033585:schizandrol B; D008095:Lithocholic Acid