title: Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury.
abstract: 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 gamma coactivator-1alpha, 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, Bcl(2), 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.
authors.affiliation: Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Mao-Meng
authors.initials: MM
authors.lastname: Tiao
authors.forename: Tsu-Kung
authors.initials: TK
authors.lastname: Lin
authors.forename: Cha-Wei
authors.initials: CW
authors.lastname: Liou
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.forename: Jin-Bor
authors.initials: JB
authors.lastname: Chen
authors.forename: Fang-Ying
authors.initials: FY
authors.lastname: Kuo
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
authors.forename: Yao-Min
authors.initials: YM
authors.lastname: Chou
authors.forename: Jiin-Haur
authors.initials: JH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000502:physiology*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; D005978:Glutathione