Kiso Shinichi, Kawata Sumio, Tamura Shinji, Inui Yoshiaki, Yoshida Yuichi, Sawai Yoshiyuki, Umeki Shinobu, Ito Nobuyuki, Yamada Akira, Miyagawa Jun-Ichiro, Higashiyama Shigeki, Iwawaki Takao, Saito Michiko, Taniguchi Naoyuki, Matsuzawa Yuji, Kohno Kenji
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Gastroenterology. 2003 Mar;124(3):701-7. doi: 10.1053/gast.2003.50097.
BACKGROUND & AIMS: 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.
METHODS & 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.
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.
肝素结合表皮生长因子样生长因子（HB-EGF）是表皮生长因子（EGF）家族的一员，以膜锚定前体（proHB-EGF）的形式合成，随后经蛋白水解加工为成熟的HB-EGF。本研究描述了在肝脏特异性表达proHB-EGF的转基因小鼠中，HB-EGF对70%部分肝切除术后肝脏再生的影响。
成年转基因小鼠与野生型小鼠之间的肝/体重比及溴脱氧尿苷（BrdU）标记指数（BrdU阳性肝细胞核的比例）无显著差异。然而，在部分肝切除术后的再生肝脏中，转基因小鼠的肝/体重比高于野生型小鼠，且在120小时时达到与部分肝切除术前相当的水平。部分肝切除术后48小时，转基因小鼠肝脏中的BrdU标记指数比野生型小鼠高约5倍（分别为51.5%和10.2%；P<0.01）。与野生型小鼠相比，部分肝切除术后转基因小鼠中微管相关蛋白激酶的激活更高且更早。部分肝切除术后肝脏中可溶性HB-EGF增加（在8分钟时），表明部分肝切除术后proHB-EGF发生了脱落。
HB-EGF的转基因表达加速了部分肝切除术后肝细胞的增殖，提示HB-EGF在体内作为一种肝营养因子发挥作用。
