Ursodeoxycholic Acid Protects against Secondary Biliary Cirrhosis in Rats by Preventing Mitochondrial Oxidative Stress

Gaetano Serviddio, Javier Pereda, Federico V. Pallardó, Julian Carretero, Consuelo Borras, Juan Cutrin, Gianluigi Vendemiale, Giuseppe Poli, José Viña, Juan Sastre

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Abstract

Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The findings of the current study indicate that UDCA partially prevents hepatic and mitochondrial glutathione depletion and oxidation resulting from chronic cholestasis. Impairment of biliary excretion was accompanied by decreased steady-state hepatic levels of γ-glutamyl cysteine synthetase and γ-cystathionase messenger RNAs. UDCA treatment led to up-regulation of γ-glutamyl cysteine synthetase in animals with secondary biliary cirrhosis and prevented the marked increases in mitochondrial peroxide production and hydroxynonenal-protein adduct production that are observed during chronic cholestasis. A population of damaged and primarily apoptotic hepatocytes characterized by dramatic decreases in mitochondrial cardiolipin levels and membrane potential as well as phosphatidylserine exposure evolves in secondary biliary cirrhosis. UDCA treatment prevents the growth of this population along with the decreases in mitochondrial cardiolipin levels and membrane potential that are induced by chronic cholestasis. In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalHepatology
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 2004

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ASJC Scopus subject areas

  • Hepatology

Cite this

Serviddio, G., Pereda, J., Pallardó, F. V., Carretero, J., Borras, C., Cutrin, J., Vendemiale, G., Poli, G., Viña, J., & Sastre, J. (2004). Ursodeoxycholic Acid Protects against Secondary Biliary Cirrhosis in Rats by Preventing Mitochondrial Oxidative Stress. Hepatology, 39(3), 711-720. https://doi.org/10.1002/hep.20101