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-beta, 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 PPARgamma expression, that enhances the inhibitory effect of the natural PPARgamma agonist 15-PGJ(2) on CTGF expression by inducing a dissociation of the SMAD2/3-CBP/p300-transcriptional complex. CONCLUSIONS: We show that caffeine strongly down-modulates TGF-beta-induced CTGF expression in hepatocytes by stimulation of degradation of the TGF-beta effector SMAD 2, inhibition of SMAD3 phosphorylation and up-regulation of the PPARgamma-receptor. Long-term caffeinization might be an option for anti-fibrotic trials in chronic liver diseases.
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-beta, 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 PPARgamma expression, that enhances the inhibitory effect of the natural PPARgamma agonist 15-PGJ(2) on CTGF expression by inducing a dissociation of the SMAD2/3-CBP/p300-transcriptional complex. CONCLUSIONS: We show that caffeine strongly down-modulates TGF-beta-induced CTGF expression in hepatocytes by stimulation of degradation of the TGF-beta effector SMAD 2, inhibition of SMAD3 phosphorylation and up-regulation of the PPARgamma-receptor. Long-term caffeinization might be an option for anti-fibrotic trials in chronic liver diseases.
Authors: Zhenyue Tong; Ruju Chen; Daniel S Alt; Sherri Kemper; Bernard Perbal; David R Brigstock Journal: Hepatology Date: 2009-09 Impact factor: 17.425
Authors: Mario G Moreno; Enrique Chávez; Liseth R Aldaba-Muruato; José Segovia; Paula Vergara; Víctor Tsutsumi; Mineko Shibayama; Yadira Rivera-Espinoza; Pablo Muriel Journal: Hepatol Int Date: 2011-01-25 Impact factor: 6.047
Authors: Anita Pathil; Jan Mueller; Johannes M Ludwig; Jiliang Wang; Arne Warth; Walee Chamulitrat; Wolfgang Stremmel Journal: Br J Pharmacol Date: 2014-09-05 Impact factor: 8.739
Authors: Jun Wei; Asish K Ghosh; Jennifer L Sargent; Kazuhiro Komura; Minghua Wu; Qi-Quan Huang; Manu Jain; Michael L Whitfield; Carol Feghali-Bostwick; John Varga Journal: PLoS One Date: 2010-11-02 Impact factor: 3.240