Rudnick David A, Liao Yunjun, An Jae-Koo, Muglia Louis J, Perlmutter David H, Teckman Jeffrey H
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hepatology. 2004 Apr;39(4):1048-55. doi: 10.1002/hep.20118.
alpha-1-Antitrypsin (alpha1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant alpha-1-antitrypsin Z (alpha1-ATZ) molecule retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of alpha1-AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild-type mice. Hepatic alpha1-AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular alpha1-ATZ accumulation. Testosterone treatment of female PiZ mice increased alpha1-ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular alpha1-AT globules had a proliferative advantage compared with globule-containing hepatocytes. However, this advantage is relative because both globule-containing and globule-devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant alpha1-ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender-specific signals influence the degree of alpha1-AT expression and associated hepatic injury, and that hepatocytes devoid of alpha1-ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases.
α-1抗胰蛋白酶（α1-AT）缺乏症是小儿代谢性肝病最常见的病因。肝细胞损伤是由滞留在肝细胞内的突变型α-1抗胰蛋白酶Z（α1-ATZ）分子的毒性所致。在这些研究中，我们使用α1-AT缺乏症的PiZ转基因小鼠模型，来研究对这种代谢性疾病所致慢性肝损伤的肝细胞增殖情况。结果显示，与雌性PiZ小鼠和野生型小鼠相比，雄性PiZ小鼠的肝细胞增殖增加且半胱天冬酶9激活。雄性PiZ小鼠肝脏中的α1-AT mRNA和蛋白表达也增加，这表明雄性中更大程度的肝细胞增殖和半胱天冬酶激活是由于与更多细胞内α1-ATZ积累相关的肝毒性增加所致。用睾酮治疗雌性PiZ小鼠可使α1-ATZ表达和肝细胞增殖增加至与雄性相当的水平。在PiZ小鼠中，不含细胞内α1-AT小球的肝细胞比含小球的肝细胞具有增殖优势。然而，这种优势是相对的，因为在部分肝切除术后，含小球和不含小球的肝细胞均表现出相当的增殖。总之，这些数据表明，突变型α1-ATZ的细胞内滞留与导致肝细胞增殖增加的再生刺激相关，性别特异性信号影响α1-AT表达程度及相关肝损伤，且不含α1-ATZ的肝细胞比积累突变蛋白的细胞具有增殖优势。这种选择性增殖表明肝细胞移植可能适用于治疗这种及其他缓慢进展的代谢性肝病。
