Pharmacological application of caffeine inhibits TGF-β-stimulated connective tissue growth factor expression in hepatocytes via PPARγ and SMAD2/3-dependent pathways

Background/Aims Epidemiological studies suggest that coffee drinking is inversely correlated with the risk of development of liver fibrosis but the molecular basis is unknown. Methods We investigated the pharmacological mechanisms involved in caffeine-dependent regulation of CTGF expression, an important modulator protein of fibrogenic TGF-β, in rat hepatocytes using Western-blot, co-immunoprecipitations, reporter-gene-assays and ELISAs. Results It is demonstrated that caffeine, similar to 8-Br-cAMP, suppresses CTGF expression, decreases SMAD2 protein levels and inhibits SMAD1/3-phosphorylation. The SMAD2 level can be restored by a proteasome inhibitor. Additionally, caffeine leads to an up-regulation of PPARγ expression, that enhances the inhibitory effect of the natural PPARγ agonist 15-PGJ2 on CTGF expression by inducing a dissociation of the SMAD2/3-CBP/p300-transcriptional complex. Conclusions We show that caffeine strongly down-modulates TGF-β-induced CTGF expression in hepatocytes by stimulation of degradation of the TGF-β effector SMAD 2, inhibition of SMAD3 phosphorylation and up-regulation of the PPARγ-receptor. Long-term caffeinization might be an option for anti-fibrotic trials in chronic liver diseases.