Collantes María, Serrano-Mendioroz Irantzu, Benito Marina, Molinet-Dronda Francisco, Delgado Mercedes, Vinaixa María, Sampedro Ana, Enríquez de Salamanca Rafael, Prieto Elena, Pozo Miguel A, Peñuelas Iván, Corrales Fernando J, Barajas Miguel, Fontanellas Antonio
MicroPET Research Unit, CIMA-CUN, University of Navarra, Pamplona, Spain, Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain, Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain.
Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Hum Mol Genet. 2016 Apr 1;25(7):1318-27. doi: 10.1093/hmg/ddw013. Epub 2016 Jan 21.
Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver.
卟啉胆色素原脱氨酶（PBGD）单倍剂量不足（急性间歇性卟啉症，AIP）的特征是，当肝脏血红素合成被包括禁食在内的内源性或环境因素激活时，会出现神经内脏发作。虽然已经描述了肝脏血红素合成营养调节的分子机制，但卟啉症患者在禁食期间的葡萄糖稳态仍知之甚少。我们的研究旨在分析PBGD缺陷小鼠在禁食期间的葡萄糖稳态和肝脏碳水化合物代谢。为了确定肝脏PBGD缺陷对碳水化合物代谢的影响，我们纳入了注射了PBGD肝脏基因传递载体的AIP小鼠。禁食14小时后，血清和肝脏代谢组学分析表明，野生型小鼠刺激肝脏糖原降解以维持葡萄糖稳态，而AIP小鼠的肝脏由于无法利用储存的糖原而激活糖异生和酮体生成。禁食的AIP小鼠血清中胰岛素浓度升高，胰高血糖素水平降低。肝脏中PBGD蛋白的特异性过表达倾向于使循环胰岛素和胰高血糖素水平正常化，刺激肝脏糖原分解并阻止酮体产生。在禁食的AIP小鼠的初级体感脑皮质中观察到葡萄糖摄取减少，这可通过PBGD肝脏基因传递来逆转。总之，通过肝脏碳水化合物代谢改变和脑皮质葡萄糖消耗改变来衡量，AIP小鼠对禁食表现出不同的反应。在肝脏中恢复PBGD基因表达后，禁食的AIP小鼠的葡萄糖稳态有效地恢复正常。
