The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis

摘要: Background & Aims: The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits acid synthesis by inducing small heterodimer partner (SHP) gene expression. aim of this study was to investigate whether FXR expressed modulates function hepatic stellate cells (HSCs). Methods: antifibrotic activity ligand tested in 2 rodent models: the porcine serum duct ligation (BDL). Results: Twelve-week administration 1–10 mg/kg 6-ethyl chenodeoxycholic (6-ECDCA), a synthetic ligand, serum-treated rats prevented liver fibrosis development reduced expression α1(I) collagen, TGF-β1 α-SMA mRNA ∼90%. Therapeutic 6-ECDCA, 3 mg/kg, BDL transforming growth factor (TGF)-β1, α-SMA, tissue metalloproteinase inhibitor (TIMP)-1 messenger RNA (mRNA) 70%–80%. No protection observed treated with CDCA, ursodeoxycholic acid, 15 mg/kg. detected HSCs. Exposure HSCs ligands caused 3-fold increase SHP, α1(I)collagen ∼60%–70% abrogates collagen up-regulation induced thrombin TGF-β1. By retrovirus infection interference RNA, we generated SHP overexpressing SHP-deficient HSC-T6. Using these cell lines, demonstrated that binds JunD DNA binding adaptor protein (AP)-1 thrombin. Conclusions: demonstrating FXR-SHP regulatory cascade promotes resolution fibrosis, establish might represent novel therapeutic option treat fibrosis.