RGD Reference Report - Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. - Rat Genome Database

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

Authors: Gressner, OA  Lahme, B  Rehbein, K  Siluschek, M  Weiskirchen, R  Gressner, AM 
Citation: Gressner OA, etal., J Hepatol. 2008 Nov;49(5):758-67. Epub 2008 Apr 30.
RGD ID: 2301880
Pubmed: PMID:18486259   (View Abstract at PubMed)
DOI: DOI:10.1016/j.jhep.2008.03.029   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to caffeine  IEP 2301880 RGD 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Ep300  (E1A binding protein p300)
Pparg  (peroxisome proliferator-activated receptor gamma)
Smad2  (SMAD family member 2)
Smad3  (SMAD family member 3)


Additional Information