Sinclair Elaine M, Yusta Bernardo, Streutker Catherine, Baggio Laurie L, Koehler Jacqueline, Charron Maureen J, Drucker Daniel J
Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
Gastroenterology. 2008 Dec;135(6):2096-106. doi: 10.1053/j.gastro.2008.07.075. Epub 2008 Aug 3.
BACKGROUND & AIMS: Glucagon action in the liver is essential for control of glucose homeostasis and the counterregulatory response to hypoglycemia. Because receptors for the related peptides glucagon-like peptide-1 and glucagon-like peptide-2 regulate beta-cell and enterocyte apoptosis, respectively, we examined whether glucagon receptor (Gcgr) signaling modulates hepatocyte survival.
The importance of the Gcgr for hepatocyte cell survival was examined using Gcgr+/+ and Gcgr-/- mice in vivo, and murine hepatocyte cultures in vitro.
Gcgr-/- mice showed enhanced susceptibility to experimental liver injury induced by either Fas Ligord activation or a methionine- and choline-deficient diet. Restoration of hepatic Gcgr expression in Gcgr-/- mice attenuated the development of hepatocellular injury. Furthermore, exogenous glucagon administration reduced Jo2-induced apoptosis in wild-type mice and decreased caspase activation in fibroblasts expressing a heterologous Gcgr and in primary murine hepatocyte cultures. The anti-apoptotic actions of glucagon were independent of protein kinase A, phosphatidylinositol-3K, and mitogen-activated protein kinase, and were mimicked by the exchange protein directly activated by the cyclic AMP agonist 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate-cAMP.
These findings extend the essential actions of the Gcgr beyond the metabolic control of glucose homeostasis to encompass the regulation of hepatocyte survival.
胰高血糖素在肝脏中的作用对于控制葡萄糖稳态及对低血糖的反调节反应至关重要。由于相关肽类胰高血糖素样肽-1和胰高血糖素样肽-2的受体分别调节β细胞和肠上皮细胞凋亡，我们研究了胰高血糖素受体（Gcgr）信号传导是否调节肝细胞存活。
使用野生型和Gcgr基因敲除小鼠在体内以及小鼠肝细胞培养物在体外研究Gcgr对肝细胞存活的重要性。
Gcgr基因敲除小鼠对由Fas配体激活或蛋氨酸和胆碱缺乏饮食诱导的实验性肝损伤表现出更高的易感性。在Gcgr基因敲除小鼠中恢复肝脏Gcgr表达可减轻肝细胞损伤的发展。此外，外源性给予胰高血糖素可减少野生型小鼠中Jo2诱导的凋亡，并降低在表达异源Gcgr的成纤维细胞和原代小鼠肝细胞培养物中的半胱天冬酶激活。胰高血糖素的抗凋亡作用独立于蛋白激酶A、磷脂酰肌醇-3激酶和丝裂原活化蛋白激酶，并且可被环磷酸腺苷激动剂8-（4-氯苯硫基）-2'-O-甲基腺苷-3'，5'-环一磷酸-cAMP直接激活的交换蛋白模拟。
这些发现将Gcgr的重要作用从葡萄糖稳态的代谢控制扩展到包括肝细胞存活的调节。
