Protection against hepatocyte mitochondrial dysfunction delays fibrosis progression in mice.
Accumulating evidence indicates that oxidative stress is involved in the physiopathology of liver fibrogenesis. However, amid the global context of hepatic oxidative stress, the specific role of hepatocyte mitochondrial dysfunction in the fibrogenic process is still unknown. The aim of this study was to determine whether a targeted protection of hepatocytes against mitochondrial dysfunction could modulate fibrosis progression. We induced liver fibrogenesis by chronic carbon tetrachloride treatment (3 or 6 weeks of biweekly injections) in transgenic mice expressing Bcl-2 in their hepatocytes or in normal control mice. Analyses of mitochondrial DNA, respiratory chain complexes, and lipid peroxidation showed that Bcl-2 transgenic animals were protected against mitochondrial dysfunction and oxidative stress resulting from carbon tetrachloride injury. Picrosirius red staining, alpha-smooth muscle actin immunohistochemistry, and real-time PCR for transforming growth factor-beta and collagen alpha-I revealed that Bcl-2 transgenic mice presented reduced fibrosis at early stages of fibrogenesis. However, at later stages increased nonmitochondrial/nonhepatocytic oxidative stress eventually overcame the capacity of Bcl-2 overexpression to prevent the fibrotic process. In conclusion, we demonstrate for the first time that specific protection against hepatocyte mitochondrial dysfunction plays a preventive role in early stages of fibrogenesis, delaying its onset. However, with the persistence of the aggression, this protection is no longer sufficient to impede fibrosis progression.
Mitchell
Claudia
C
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Fance.
Robin
Marie-Anne
MA
Mayeuf
Alicia
A
Mahrouf-Yorgov
Meriem
M
Mansouri
Abdellah
A
Hamard
Marie
M
Couton
Dominique
D
Fromenty
Bernard
B
Gilgenkrantz
Hélène
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; D002251:Carbon Tetrachloride; D020169:Caspases