title: Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism.
abstract: Obstructive cholestasis is characterized by impairment of hepatic canalicular bile efflux and there are no clinically effective drugs to cure except surgeries. Previously we revealed that oleanolic acid (OA) protected against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice. Cholestasis caused by LCA is characterized by segmental bile duct obstruction, whether OA possesses the beneficial effect on completed obstructive cholestasis induced by bile duct ligation (BDL) remains unknown. In this study, we demonstrated that BDL-induced mice liver pathological change, and increase in serum levels of ALT, AST and ALP were all significantly reduced by OA (20 mg/kg, i.p.). Meanwhile, OA also lowered total bilirubin and total bile acids levels in serum, as well as total bile acids level in liver, in contrast, urinary total bile acids output was remarkably up-regulated by OA. Gene expression analysis showed that OA caused significant increased mRNA expression of MRP3 and MRP4 located at hepatic basolateral membrane, and restoration of MRP2 and BSEP located at hepatic cannalicular membrane. Furthermore, significant NRF2 protein accumulation in nucleus was also observed in OA treated mice. In mice primary cultured hepatocytes, the effects of OA on MRP2, MRP3 and MRP4 expression were directly proved to be mediated via NRF2 activation, and BSEP downregulation induced by OA was in part due to FXR antagonism. Luciferase assay performed in Hep G2 cells also illustrated that OA was a partial FXR antagonist. Taken together, we conclude that OA attenuates obstructive cholestasis in BDL mice, possibly via activation of NRF2-MRPs and FXR antagonism.
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China.
authors: Pan
authors: P
authors: Chen
authors: Center of Reproductive Medicine, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, PR China.
authors: Jingjie
authors: J
authors: Li
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China.
authors: Xiaomei
authors: X
authors: Fan
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Hang
authors: H
authors: Zeng
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China.
authors: Rongrong
authors: R
authors: Deng
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Dongshun
authors: D
authors: Li
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Min
authors: M
authors: Huang
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: bihchang@mail.sysu.edu.cn.
authors: Huichang
authors: H
authors: Bi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002779:Cholestasis / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000819:agonists / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D009828:Oleanolic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C495636:Nfe2l2 protein, mouse
keywords: Bile duct ligation; Cholestasis; FXR; MRP; NRF2; Oleanolic acid