Gene transfer of IGF1 attenuates hepatocellular apoptosis after bile duct ligation.
BACKGROUND
Cholestasis occurs in a wide variety of human liver diseases, and hepatocellular injury is an invariant feature of cholestasis, causing liver dysfunction and inflammation, promoting fibrogenesis, and ultimately leading to liver failure. Insulin-like growth factor 1 (IGF1) acts in an autocrine and paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3 K)/Akt, the downstream glycogen synthase kinase 3β (GSK3β), and anti-apoptotic pathways. This study investigated whether gene transfer of IGF1 could attenuate hepatocellular injury after bile duct ligation in rats.


METHODS
Experiments were performed in 80 male Sprague-Dawley rats. Thirty minutes after bile duct ligation, hydrodynamics-based gene transfection with IGF1 plasmid via rapid tail vein injection. The rats were randomly divided into the following four groups: sham operated; BDL treated with pCMV-IGF1 gene; BDL treated with vehicle for pCMV-LacZ gene; and BDL only.


RESULTS
IGF1 expression in liver after a single administration of IGF-1 plasmid was demonstrated. Liver function index, including serum alanine aminotransferase and aspartate aminotransferase, were significantly reduced in IGF1 gene transfer rats. We determined the mechanism of IGF1 gene transfer after BDL in terms of activation of Akt, inhibition of GSK3β, and blockage of caspase-9 cleavage. Furthermore, hepatocyte stellate cell activation was markedly inhibited in IGF1 gene-treated rats. Apoptosis was significantly attenuated by IGF1 gene therapy.


CONCLUSIONS
This study demonstrated that gene transfer of IGF1 could attenuate hepatocellular apoptosis and injury after bile duct ligation in rats.
Pi-Chieh Wang
Kenneth
K
Department of Family Medicine, PoJen General Hospital, Taipei, Taiwan.
Lee
Liang-Ming
LM
Lin
Tien-Jen
TJ
Sheen-Chen
Shyr-Ming
SM
Lin
Jia-Wei
JW
Chiu
Wen-Ta
WT
Wang
Chien-Che
CC
Hung
Kuo-Sheng
KS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001652:Bile Ducts / Q000601:surgery*; D053453:Caspase 9 / Q000502:physiology; D002779:Cholestasis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000473:pathology* / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000502:physiology*; D008026:Ligation / Q000009:adverse effects; D008099:Liver / Q000502:physiology; D008297:Male; D010957:Plasmids / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053453:Caspase 9