Gressner Olav A, Lahme Birgit, Rehbein Katharina, Siluschek Monika, Weiskirchen Ralf, Gressner Axel M
Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, 52074 Aachen, Germany.
J Hepatol. 2008 Nov;49(5):758-67. doi: 10.1016/j.jhep.2008.03.029. Epub 2008 Apr 30.
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.
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.
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.
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.
背景/目的：流行病学研究表明，咖啡饮用与肝纤维化发生风险呈负相关，但其分子基础尚不清楚。
我们利用蛋白质免疫印迹法、免疫共沉淀法、报告基因检测法和酶联免疫吸附测定法，研究了咖啡因依赖性调节CTGF表达（一种促纤维化的转化生长因子-β的重要调节蛋白）在大鼠肝细胞中的药理机制。
结果表明，咖啡因与8-溴环磷酸腺苷类似，可抑制CTGF表达，降低SMAD2蛋白水平，并抑制SMAD1/3磷酸化。蛋白酶体抑制剂可使SMAD2水平恢复。此外，咖啡因导致PPARγ表达上调，通过诱导SMAD2/3-CBP/p300转录复合物解离，增强天然PPARγ激动剂15-前列腺素J2对CTGF表达的抑制作用。
我们发现咖啡因通过刺激转化生长因子-β效应蛋白SMAD 2的降解、抑制SMAD3磷酸化和上调PPARγ受体，强烈下调转化生长因子-β诱导的肝细胞中CTGF的表达。长期摄入咖啡因可能是慢性肝病抗纤维化试验的一种选择。
