Less Smad2 is good for you! A scientific update on coffee's liver benefits.
Scientists at the National Institutes of Health have reported that increased coffee consumption is associated with a slower progression of fibrogenesis in patients with chronic and particularly alcoholic liver disease and a reduced incidence of heptocellular carcinoma. However, a causal mechanistic explanation was pending. New results indicate that the methylxanthine caffeine--a major component of coffee and the most widely consumed pharmacologically active substance in the world--might be responsible for this phenomenon, because it inhibits the synthesis of connective tissue growth factor (CTGF/CCN2) in liver parenchymal and nonparenchymal cells, primarily by inducing degradation of Smad2 (and to a much lesser extent Smad3) and thus impairment of transforming growth factor beta (TGF-beta) signaling. CTGF and TGF-beta play crucial roles in the fibrotic remodeling of various organs, and, ultimately, carcinogenesis. This article summarizes the clinical-epidemiological observations as well as the pathophysiological background and provides suggestions for the therapeutic use of (methyl)xanthine derivatives in the management of fibro-/carcinogenic (liver) diseases.
Gressner
Olav A
OA
Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH University Hospital, Aachen, Germany. ogressner@ukaachen.de
D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D000818:Animals; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control; D024042:Collagen Type I / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000517:prevention & control; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051899:Smad2 Protein / Q000502:physiology*; D013806:Theophylline / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014970:Xanthines / Q000494:pharmacology
D024042:Collagen Type I; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D014970:Xanthines; C046736:N-acetylgalactosamine 6-sulfate; D055513:Connective Tissue Growth Factor; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline; D046988:Proteasome Endopeptidase Complex; D000116:Acetylgalactosamine; C021183:1,7-dimethylxanthine