Hepatic stellate cells (HSC) and portal myofibroblasts have been identified as key cellular players in hepatic fibrogenesis.23 In response

to chronic liver injury, HSCs undergo transdifferentiation from a quiescent to an activated myofibroblastic-like phenotype,24 a process orchestrated by several transcriptional regulators including NRs25 (Supporting Table 3). Loss of vitamin A-rich droplets and the reduction of retinoic acid (RA) contents represent a key event in the transdifferentiation process to a myofibroblastic-like phenotype. Therefore, the retinol and RA binding nuclear receptors RAR and RXR have been considered central regulators in HSC activation26 (Supporting Table 3). In line with this, supplementation of HSCs with retinol and RA prevents transdifferentiation and decreases collagen type I synthesis.27,28 www.selleckchem.com/products/PLX-4032.html PPARs also play a key role in HSC biology (Supporting Table 3). PPARγ is involved in the maintenance of a quiescent HSC phenotype. PPARγ inhibits AP-1 and profibrogenic gene expression and activation of HSC results in loss of PPARγ inhibition.29 Treatment of HSC with synthetic X-396 cost PPARγ ligands suppresses the fibrogenetic

potential of HSC in vitro and in vivo.29-31 The antifibrotic effects of curcumin are also partly mediated by PPARγ.32 PPARδ counteracts PPARγ effects by inhibiting PPARγ’s transcriptional activity33 and enhancing HSC proliferation and the expression of markers of fibrosis.34 The role of FXR in fibrosis is controversial. Stimulation of FXR has been claimed as novel therapeutic approach to treat liver fibrosis because a series of studies suggested that FXR can modulate HSC activity by restoring PPARγ and by FXR-SHP-dependent inhibition of AP-1 signaling on downstream profibrogenic targets.35-37 Interestingly, studies with FXR agonists in mice with diabetic nephropathy also showed reduction of glomerulosclerosis and tubulointerstitial fibrosis

in kidney, which could be attributed in part to direct inhibition of TGF-β in renal mesangial cells in invitro experiments.38 These data therefore suggest that the potential antifibrotic effect MCE of FXR agonists is not limited to the liver. In contrast, recent work in different mouse models of biliary type and nonbiliary type of fibrosis revealed that lack of FXR significantly reduces fibrosis of the biliary type, whereas having no impact on noncholestatic liver fibrosis.39 Notably, FXR expression could neither be detected in mouse HSCs nor myofibroblasts at biologically significant levels and was minimal in human HSCs.39 It remains open for further studies to clarify whether the antifibrotic effects of FXR are the direct consequence of modulating fibrotic effector cells and signals, or whether this may be secondary effects due to modulation of inflammation and bile acid metabolism.