Hepatocyte growth factor protects against Fas-mediated liver apoptosis in transgenic mice.
BACKGROUND
Apoptosis via the Fas/Fas ligand signalling system plays an important role in the development of various liver diseases. The administration of an agonistic anti-Fas antibody to mice causes massive hepatic apoptosis and fulminant hepatic failure. Several growth factors including hepatocyte growth factor (HGF) have been found to prevent apoptosis.


METHODS
In this study, we demonstrated the overexpression of HGF to have a protective effect on Fas-mediated hepatic apoptosis using a transgenic mice (Tg mice) model.


RESULTS
In HGF Tg mice, the elevation of alanine aminotransferase was dramatically inhibited at 12 and 24 h after the administration of 0.15 mg/kg anti-Fas antibody. HGF Tg mice showed a significantly lower number of apoptotic hepatocytes at 12 h compared with wild-type (WT) mice. Furthermore, 85% (six of seven) HGF Tg mice were able to survive after the administration of 0.3 mg/kg anti-Fas antibody, while none of the WT mice survived. The Bcl-xL expression was increased in HGF Tg mice, while there was no difference in the expression of Bax, Bid, Mcl-1 and bcl-2 between WT mice and HGF Tg mice. In addition, the HGF Tg mice showed more Akt phosphorylation than the WT mice both before and after the anti-Fas antibody injection.


CONCLUSIONS
Taken together, our findings suggest that HGF protects against Fas-mediated liver apoptosis in vivo, and the upregulation of Bcl-xL via Akt activation may also play a role in the protective effects of HGF.
Suzuki
Hideyuki
H
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Toyoda
Mitsuo
M
Horiguchi
Norio
N
Kakizaki
Satoru
S
Ohyama
Tatsuya
T
Takizawa
Daichi
D
Ichikawa
Takeshi
T
Sato
Ken
K
Takagi
Hitoshi
H
Mori
Masatomo
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000032:analysis; D051020:bcl-X Protein / Q000032:analysis; D019014:fas Receptor / Q000502:physiology*
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; D017228:Hepatocyte Growth Factor; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt