Glucagon contributes to liver zonation in mice [Gcg KO]

Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway. Gene expression profiling of Gcg-/- and wild type mice in liver肝脏分区代谢（Liver zonation）指代谢通路沿肝小叶的空间分隔，是肝脏实现最优功能的必要条件。Wnt/β-连环蛋白（Wnt/beta-catenin）信号通路通过激活静脉周肝细胞内的基因、同时抑制门周肝细胞内的对应基因，调控肝脏的代谢分区。本研究证实，胰高血糖素可拮抗Wnt/β-连环蛋白信号通路对基因表达及代谢分区模式的调控作用。该拮抗效应在门周肝细胞中更为显著：其中28%的基因可被胰高血糖素激活，同时被Wnt/β-连环蛋白信号通路抑制。胰高血糖素与Wnt/β-连环蛋白的受体及其信号通路在门周及静脉周肝细胞中均匀分布，且其表达不受上述拮抗信号的调控。综上，本研究结果表明，胰高血糖素可通过与Wnt/β-连环蛋白信号通路的拮抗作用，调控肝脏内的基因表达与代谢分区。本研究针对Gcg基因敲除（Gcg-/-）小鼠与野生型小鼠的肝脏开展了基因表达谱分析。