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Caffeine prevents experimental liver fibrosis by blocking the expression of TGF-

Arauz, Jonathana; Zarco, Natanaelb; Segovia, Joséb; Shibayama, Minekoc; Tsutsumi, Victorc; Muriel, Pabloa

European Journal of Gastroenterology & Hepatology: February 2014 - Volume 26 - Issue 2 - p 164–173
doi: 10.1097/MEG.0b013e3283644e26
Original Articles: Liver Fibrosis

Background: There is a growing body of evidence that caffeine exerts beneficial effects on the liver; however, the molecular mechanisms by which caffeine exerts beneficial effects on the liver are poorly defined.

Aims: The aim of the present study was to examine the efficacy of caffeine in preventing thioacetamide (TAA)-induced cirrhosis in rats.

Materials and methods: Cirrhosis was induced by chronic TAA administration and the effects of coadministration of caffeine for 8 weeks were evaluated, including control groups.

Results: The administration of TAA induced liver cirrhosis, which was inhibited by caffeine. Caffeine prevents elevation of liver enzymes. Liver histopathology and hydroxyproline levels were significantly lower in the rats treated with TAA plus caffeine compared with TAA only. Caffeine shows antioxidant properties by restoring the redox equilibrium [lipid peroxidation and glutathione peroxidase (GPx) levels]. Western blot assays showed blockade of the expression of transforming growth factor-β and its downstream inductor connective tissue growth factor. Similarly, caffeine decreases messenger RNA levels of these profibrogenic proteins. In addition, caffeine inhibits hepatic stellate cells because of blockade of the expression of α-smooth muscle actin; in the western blot assay, we also found low levels of mRNA of collagen α1. Zymography assays showed that caffeine had an effect on the activity of matrix metalloproteinases 2 and 9, but no effect on the expression of tissue inhibitor of metalloproteinases-1, using RT-PCR.

Conclusion: Our results show that caffeine prevents experimental cirrhosis; the mechanisms of action are associated with its antioxidant properties and mainly by its ability to block the elevation of the profibrogenic cytokine transforming growth factor-β, which may be associated with attenuation of the inflammatory and fibrotic processes.

Departments of aPharmacology

bPhysiology, Biophysics and Neuroscience

cInfectomics and Molecular Pathogenesis, Cinvestav-IPN., Mexico, D.F. Mexico

Correspondence to Pablo Muriel, PhD, Department of Pharmacology, Cinvestav-I.P.N. Apdo. Postal 14-740, Mexico 07000, D.F., Mexico Tel: +52 55 5747 3303; fax: +52 55 5747 3394; e-mail: pamuriel@cinvestav.mx

Received April 9, 2013

Accepted June 17, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins