Abstract:

Objective    To study effects of nuclear factor–E2-related factor2(Nrf2) on cholestasis in mice after common bile duct ligation(BDL). Methods    Wild type(WT) and Nrf2 knockout (KO) mice underwent BDL. Liver function, histological morphology, mitogen-activated protein kinase (MAPK) signals and some mRNAs were studied. Results    After BDL, levels of serum total bilirubin(TBIL) and alanine aminotransferase(ALT) were significantly increased compared with the sham(no BDL) group: the level of ALT was higher in KO mice than in WT mice, while TBIL was the reverse. Fibronectine(FN) was more expressed in KO mice than in WT mice. Western blot showed phosphorylations of cJun N-terminal kinases(JNK), activator of transcription 3(stat3), protein kinase B(PKB/AKT) and p38 after BDL were stronger in WT mice, while phosphorylation of extracellular signal-regulated kinase(ERK) was stronger in KO mice. RNAase protection assay(RPA) showed that mRNA levels of some Nrf2 target genes were up-regulated after BDL. Inductions of NAD(P)H quinine oxidoreductase 1(NQO1), glutathione S-transferase (GST)Ya and GST-pa expressions were attenuated in KO mice. Expressions of transforming growth factorβ1(TGF-β1)， tissue inhibitors of metalloproteinases-1(TIMP-1) and collagen1 were up-regulated after BDL, and more greatly in KO mice. Conclusion     Nrf2 has an effect on MAPK signals, inflammation and fibrosis in liver injury during cholestasis, partly via the upregulation of anti-oxidation genes for cell protection.

Key words: Cholestasis; Nuclear factor–E2-related factor2; Mice; Liver injury