Sekine Shigeki, Lan Billy Yu-Ang, Bedolli Melanie, Feng Sandy, Hebrok Matthias
Department of Medicine, Diabetes Center, University of California--San Francisco, San Francisco, CA 94143-0573, USA.
Hepatology. 2006 Apr;43(4):817-25. doi: 10.1002/hep.21131.
There is accumulating evidence that Wnt/beta-catenin signaling is involved in the regulation of liver development and physiology. The presence of genetic alterations resulting in constitutive beta-catenin stabilization in human and murine liver tumors also implicates this pathway in hepatocyte proliferation. In the present study, we generated hepatocyte-specific beta-catenin knockout mice to explore the role of beta-catenin in liver function. Conditional knockout mice were born at the expected Mendelian ratio and developed normally to adulthood, indicating beta-catenin is dispensable for essential liver function under normal breeding conditions. However, the liver mass of knockout mice was 20% less than those of mice in the control groups. Expression analysis revealed loss of genes required for glutamine synthesis in knockout mice. Loss of the liver glutamine synthesis pathway did not affect the blood ammonia level in mice fed a standard diet, yet, knockout mice showed significantly elevated blood ammonia levels with high-protein dietary feeding. Furthermore, the expression of two cytochrome P450 enzymes, CYP1A2 and CYP2E1, was almost completely abolished in livers from hepatocyte-specific beta-catenin knockout mice. Consequently, these mice were resistant to acetaminophen challenge, confirming the requirement of these cytochrome P450 enzymes for metabolism of xenobiotic substances. In conclusion, in addition to regulating hepatocyte proliferation, beta-catenin may also control multiple aspects of normal liver function.
越来越多的证据表明，Wnt/β-连环蛋白信号通路参与肝脏发育和生理功能的调节。在人类和小鼠肝脏肿瘤中存在导致β-连环蛋白持续稳定的基因改变，这也表明该通路与肝细胞增殖有关。在本研究中，我们构建了肝细胞特异性β-连环蛋白基因敲除小鼠，以探讨β-连环蛋白在肝脏功能中的作用。条件性基因敲除小鼠以预期的孟德尔比例出生，并正常发育至成年，这表明在正常饲养条件下，β-连环蛋白对于肝脏基本功能并非必需。然而，基因敲除小鼠的肝脏重量比对照组小鼠轻20%。表达分析显示，基因敲除小鼠中谷氨酰胺合成所需的基因缺失。肝脏谷氨酰胺合成途径的缺失并不影响喂食标准饮食小鼠的血氨水平，但是，基因敲除小鼠在高蛋白饮食喂养时血氨水平显著升高。此外，肝细胞特异性β-连环蛋白基因敲除小鼠肝脏中两种细胞色素P450酶CYP1A2和CYP2E1的表达几乎完全消失。因此，这些小鼠对乙酰氨基酚攻击具有抗性，证实了这些细胞色素P450酶对外源物质代谢的必要性。总之，β-连环蛋白除了调节肝细胞增殖外，还可能控制正常肝脏功能的多个方面。
