Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy.
OBJECTIVE
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is synthesized in the form of a membrane-anchored precursor (proHB-EGF), which subsequently is processed proteolytically to mature HB-EGF. This study describes the effects of HB-EGF on liver regeneration after 70% partial hepatectomy in proHB-EGF transgenic mice with liver-specific expression.


RESULTS
No significant differences in liver/body weight ratios and in bromodeoxyuridine (BrdU)-labeling index (the ratios of BrdU-positive hepatocyte nuclei) were found between adult transgenic and wild-type mice. However, in regenerating liver after partial hepatectomy, transgenic mice had higher liver/body weight ratios than wild-type mice and at 120 hours reached a level equal to that before partial hepatectomy. The BrdU-labeling index was about 5 times higher in the livers of transgenic mice compared with the wild type (51.5% vs. 10.2%, respectively; P < 0.01) at 48 hours after partial hepatectomy. Activation of microtubule-associated protein kinase after partial hepatectomy was higher and earlier in the transgenic mice as compared with the wild-type mice. Soluble HB-EGF was increased in the liver (at 8 min) after partial hepatectomy, indicating that the shedding of proHB-EGF occurred after partial hepatectomy.


CONCLUSIONS
The transgenic expression of HB-EGF accelerates the proliferation of hepatocytes after partial hepatectomy, suggesting that HB-EGF functions as a hepatotrophic factor in vivo.
Kiso
Shinichi
S
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Kawata
Sumio
S
Tamura
Shinji
S
Inui
Yoshiaki
Y
Yoshida
Yuichi
Y
Sawai
Yoshiyuki
Y
Umeki
Shinobu
S
Ito
Nobuyuki
N
Yamada
Akira
A
Miyagawa
Jun-Ichiro
J
Higashiyama
Shigeki
S
Iwawaki
Takao
T
Saito
Michiko
M
Taniguchi
Naoyuki
N
Matsuzawa
Yuji
Y
Kohno
Kenji
K
D000818:Animals; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006498:Hepatectomy / Q000379:methods*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000737:chemistry; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011184:Postoperative Period; D011498:Protein Precursors / Q000378:metabolism
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011498:Protein Precursors; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases