Bile salt tauroursodeoxycholic acid modulation of Bax translocation to mitochondria protects the liver from warm ischemia-reperfusion injury in the rat.
BACKGROUND
Tauroursodeoxycholic acid (TUDC) is a hydrophilic bile acid that has a cytoprotective effect in primary biliary cirrhosis and primary sclerosing cholangitis. TUDC also protects hepatocytes from hydrophobic bile acid-induced apoptosis. The aim of this study was to determine whether TUDC ameliorates hepatocyte apoptosis during ischemia-reperfusion injury.


METHODS
We used a rat model of hepatic warm ischemia-reperfusion injury to assess the effects of TUDC. Male Sprague-Dawley rats were subjected to 1 or 2 hr of normothermic ischemia followed by 3 or 6 hr of reperfusion. The treatment group received TUDC (50 mg/kg) by bolus intravenous injection 30 min before initiation of ischemia, whereas the control group received saline only. Blood samples for biochemical analysis were obtained after 6 hr of reperfusion. Liver biopsies for histological assessment were obtained 3 and 6 hr after reperfusion. Hepatocyte apoptosis was determined by terminal dUTP nick-end labeling. The pro-apoptotic protein Bax was quantified at the mRNA and protein level.


RESULTS
Treatment with TUDC significantly reduced serum transaminase levels. This was associated with a significant amelioration in the levels of hepatocyte apoptosis in the TUDC-treated group compared with control. Furthermore, Western blot analysis of Bax expression in liver tissue indicated that TUDC inhibited the translocation of Bax from the cytosol to the mitochondria.


CONCLUSIONS
TUDC significantly reduced hepatic injury in this model. The beneficial effects of TUDC upon hepatocyte apoptosis were related to the modulation of Bax protein translocation.
Ishigami
F
F
First Department of Surgery, Shiga University of Medical Science, Seta-tsukinowacho, Otsu, Shiga 520-2192, Japan.
Naka
S
S
Takeshita
K
K
Kurumi
Y
Y
Hanasawa
K
K
Tani
T
T
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D019610:Cytoprotection; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D001219:Aspartate Aminotransferases