Regulación de la fibrogénesis hepática por la UPR y la proteína COMP

Abstract

Fibrogenic activity of hepatic stellate cells (HSC) has been shown to be regulated by different factors, including protein homeostasis and interaction with components of the extracellular matrix (ECM). Aim: We hypothesized that the response to ER stress (unfolded protein response, UPR) and the matricellular protein COMP (Cartilage Oligomeric Matrix Protein), may modulate the generation of collagen type I in HSC, and as a result the fibrogenic reponse in the liver. Results: The UPR inducer Brefeldin A (BFA) increased collagen type I levels in HSC at non-apoptotic doses. This effect was due to enhanced mRNA levels and required protein synthesis. BFA activated ERK, JNK and p38 MAPK kinases, although only p38 MAPK was involved in the fibrogenic action of BFA. Transcription factors Smad2/3 seem to mediate this profibrogenic effect, since nuclear phosphorylated levels of both proteins were increased in response to BFA treatment. Moreover, a specific inhibitor for Smad3 phosphorylation completely prevented collagen increase in HSC treated with BFA. Nuclear protein levels of C/EBPbeta were also enhanced in BFA-treated HSC, suggesting a role for this transcription factor. Increased levels of p-Smad3 in response to BFA were prevented by the p38 MAPK inhibitor SB203580, pointing to this kinase as a regulator for this factor. We also showed the UPR branch mediated by IRE1alpha activation to be involved in the enhancement of collagen type I levels and in activation of Smad3. Regarding the effects of COMP, studies performed in animal models for liver injury using knock out mice, showed COMP absence exerted a hepatoprotective effect, with decreased injury and collagen type I deposition in comparison with WT mice. In addition, rCOMP treatment caused an increase in collagen type I production by HSC that correlated with enhanced ERK and Akt phosphorylation and MMP2, 9, and 13 induction. Conclusions: These results suggest that the UPR and COMP could play a role in regulating collagen I production in HSC, which in turn may contribute to the fibrogenic response.