Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Gastrointest Liver Physiol. 2020 May 1;318(5):G912-G927. doi: 10.1152/ajpgi.00294.2019. Epub 2020 Mar 16.
Glucagon regulates the hepatic amino acid metabolism and increases ureagenesis. Ureagenesis is activated by -acetylglutamate (NAG), formed via activation of -acetylglutamate synthase (NAGS). With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we investigated whether glucagon receptor-mediated activation of ureagenesis is required in a situation where NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle in vivo. Female C57BL/6JRj mice treated with a glucagon receptor antagonist (GRA), glucagon receptor knockout () mice, and wild-type () littermates received an intraperitoneal injection of -carbamoyl glutamate (Car; a stable variant of NAG), l-citrulline (Cit), Car and Cit (Car + Cit), or PBS. In separate experiments, and mice were administered -carbamoyl glutamate and l-citrulline (Car + Cit) in the drinking water for 8 wk. Car, Cit, and Car + Cit significantly ( < 0.05) increased plasma urea concentrations, independently of pharmacological and genetic disruption of glucagon receptor signaling ( = 0.9). Car increased blood glucose concentrations equally in GRA- and vehicle-treated mice ( = 0.9), whereas the increase upon Car + Cit was impaired in GRA-treated mice ( = 0.008). Blood glucose concentrations remained unchanged in mice upon Car ( = 0.2) and Car + Cit ( = 0.9). Eight weeks administration of Car + Cit did not change blood glucose ( > 0.2), plasma amino acid ( > 0.4), and urea concentrations ( > 0.3) or the area of glucagon-positive cells ( > 0.3) in and mice. Our data suggest that glucagon-mediated activation of ureagenesis is not required when NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle. Hepatic ureagenesis is essential in amino acid metabolism and is importantly regulated by glucagon, but the exact mechanism is unclear. With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we here show, contrary to our hypothesis, that glucagon receptor-mediated activation of ureagenesis is not required when -acetylglutamate synthase activity and/or -acetylglutamate levels are sufficient to activate the first step of the urea cycle in vivo.
胰高血糖素调节肝脏氨基酸代谢并增加尿素生成。尿素生成通过 - 乙酰谷氨酸（NAG）激活，NAG 通过 - 乙酰谷氨酸合酶（NAGS）的激活形成。为了确定胰高血糖素在急性和慢性调节尿素生成的步骤，我们研究了在 NAGS 活性和/或 NAG 水平足以在体内激活尿素循环的第一步的情况下，是否需要胰高血糖素受体介导的尿素生成激活。用胰高血糖素受体拮抗剂（GRA）处理的雌性 C57BL/6JRj 小鼠、胰高血糖素受体敲除（）小鼠和野生型（）同窝小鼠接受了 - 氨甲酰谷氨酸（Car；NAG 的稳定变体）、L-瓜氨酸（Cit）、Car 和 Cit（Car + Cit）或 PBS 的腹腔内注射。在单独的实验中，和小鼠在饮用水中给予 - 氨甲酰谷氨酸和 L-瓜氨酸（Car + Cit）8 周。Car、Cit 和 Car + Cit 均显著（<0.05）增加了血浆尿素浓度，而不依赖于胰高血糖素受体信号传导的药理学和遗传破坏（=0.9）。Car 在 GRA 处理和载体处理的小鼠中同样增加了血糖浓度（=0.9），而 Car + Cit 的增加在 GRA 处理的小鼠中受损（=0.008）。Car 在小鼠中对血糖浓度没有影响（=0.2）和 Car + Cit（=0.9）。8 周给予 Car + Cit 不会改变血糖（>0.2）、血浆氨基酸（>0.4）和尿素浓度（>0.3）或胰高血糖素阳性细胞的面积（>0.3）在和小鼠中。我们的数据表明，当 NAGS 活性和/或 NAG 水平足以激活尿素循环的第一步时，胰高血糖素介导的尿素生成激活不是必需的。肝脏尿素生成在氨基酸代谢中是必不可少的，并且受到胰高血糖素的重要调节，但确切的机制尚不清楚。为了确定胰高血糖素在急性和慢性调节尿素生成的步骤，我们在这里显示，与我们的假设相反，当 - 乙酰谷氨酸合酶活性和/或 - 乙酰谷氨酸水平足以在体内激活尿素循环的第一步时，胰高血糖素受体介导的尿素生成激活不是必需的。
