Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury

Mitochondria are known to be involved in cholestatic liver injury, but the damage and biogenesis of mitochondria in response to the early stage of cholestasis is unknown. A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneous creation of the sham group receiving la...

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Bibliographic Details
Published in:Apoptosis (London) 2009-07, Vol.14 (7), p.890-899
Main Authors: Tiao, Mao-Meng, Lin, Tsu-Kung, Liou, Cha-Wei, Wang, Pei-Wen, Chen, Jin-Bor, Kuo, Fang-Ying, Huang, Chao-Cheng, Chou, Yao-Min, Chuang, Jiin-Haur
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Biology
Cholestasis - metabolism
Cholestasis - pathology
Deregulation
Glutathione - metabolism
Humans
Liver
Liver - metabolism
Liver - pathology
Male
Mitochondria, Liver - physiology
Mitochondrial DNA
Oncology
Original Paper
Oxidation-Reduction
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Rats
Rats, Sprague-Dawley
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Virology
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Summary:Mitochondria are known to be involved in cholestatic liver injury, but the damage and biogenesis of mitochondria in response to the early stage of cholestasis is unknown. A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneous creation of the sham group receiving laparotomy without BDL. A significant decrease of liver peroxisome proliferators-activated receptor γ coactivator-1α, mitochondrial transcriptional factor A (Tfam) and glutathione peroxidase (GPx) mRNA and Tfam protein from 6 to 72 h after BDL was found, which was associated with significant decrease of the glutathione, GPx and catalase activity at 72 h. At 72 h after BDL, mitochondrial DNA copy number reached the lowest level, while caspase 9 and 3 activity, but not caspase 8, Bax, Bcl₂, Fas L and Fas-Fas L complex, were upregulated significantly in the liver homogenates of BDL rats. The apoptotic liver cells appeared in large amounts in the rat liver by 72 h after BDL. Our results indicate that transcriptional regulation of the mitochondrial biogenesis is impaired within a few hours after complete bile duct obstruction, resulting in later mitochondrial dysfunction and consequent cholestatic liver injury via the intrinsic apoptosis pathway.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-009-0357-3