PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis.
PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis.
复制标题
DOI：
10.1016/j.jhep.2013.02.020
复制
发表时间：
2013-07
影响因子：
25.7
通讯作者：
Perales, Jose C.
中科院分区：
文献类型：
--
作者：
Mendez-Lucas, Andres;Duarte, Joao Andre Goncalves;Sunny, Nishanth E.;Satapati, Santhosh;He, TianTeng;Fu, Xiaorong;Bermudez, Jordi;Burgess, Shawn C.;Perales, Jose C.
肝脏再生通过补偿营养供应的不连续性来帮助维持全身能量稳态。肝特异性细胞溶质磷酸烯醇式丙酮酸羧激酶（PEPCK-C）的缺失消除了线粒体底物的再生，解除了脂质代谢的调节并影响了TCA循环。虽然小鼠肝脏几乎只表达PEPCK-C，但人类同样存在线粒体同工酶（PEPCK-M）。尽管与人体生理学有明确的相关性，但PEPCK-M的作用及其致炎潜力仍然未知。在这里，我们测试了PEPCK-M在肝脏特异性PEPCK-C敲除小鼠和WT小鼠中的胚胎发生和TCA循环功能中的意义。PEPCK-M的过度表达的影响进行了检查的示踪研究和分子生物学技术的组合。部分PEPCK-C再表达用作阳性对照。通过NMR使用2 H和13 C示踪剂在离体肝脏中评价代谢通量。在体内和原代肝细胞中研究了葡萄糖异生潜力和代谢特征。PEPCK-M表达部分挽救了PEPCK-C缺失导致的脂质代谢、血管生成和TCA循环功能受损的缺陷，而~10%的PEPCK-C再表达使大多数参数正常化。当PEPCK-M在PEPCK-C的存在下表达时，线粒体同工酶放大了总的产酶能力，这表明草酰乙酸到磷酸烯醇丙酮酸通量的自主调节是由个体同工型进行的。我们的结论是，PEPCK-M本身具有致炎潜力，并与PEPCK-C合作，以调节致炎/TCA流量，以改变底物或能量的可用性，暗示在人体肝脏中的葡萄糖和脂质代谢的调节作用。
Hepatic gluconeogenesis helps maintain systemic energy homeostasis by compensating for discontinuities in nutrient supply. Liver specific deletion of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) abolishes gluconeogenesis from mitochondrial substrates, deregulates lipid metabolism and affects TCA cycle. While, mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). Despite clear relevance to human physiology, the role of PEPCK-M and its gluconeogenic potential remain unknown. Here, we test the significance of PEPCK-M in gluconeogenesis and TCA cycle function in liver-specific PEPCK-C knockout and WT mice. The effects of the overexpression of PEPCK-M were examined by a combination of tracer studies and molecular biology techniques. Partial PEPCK-C re-expression was used as a positive control. Metabolic fluxes were evaluated in isolated livers by NMR using 2H and 13C tracers. Gluconeogenic potential, together with metabolic profiling, were investigated in vivo and in primary hepatocytes. PEPCK-M expression partially rescued defects in lipid metabolism, gluconeogenesis and TCA cycle function impaired by PEPCK-C deletion, while ~10% re-expression of PEPCK-C normalized most parameters. When PEPCK-M was expressed in the presence of PEPCK-C, the mitochondrial isozyme amplified total gluconeogenic capacity, suggesting autonomous regulation of oxaloacetate to phosphoenolpyruvate fluxes by the individual isoforms. We conclude that PEPCK-M has gluconeogenic potential per se, and cooperates with PEPCK-C to adjust gluconeogenic/TCA flux to changes in substrate or energy availability, hinting at a role in the regulation of glucose and lipid metabolism in human liver.
登录
查看更多内容
影响因子：
4.8
作者：
Lambeth, DO;Tews, KN;Milavetz, BI
通讯作者：
Milavetz, BI
影响因子：
15.9
作者：
LANDAU, BR;WAHREN, J;KALHAN, SC
通讯作者：
KALHAN, SC
肝脏中的 Pck1 基因沉默可改善 db/db 小鼠的血糖控制、胰岛素敏感性和血脂异常。
影响因子：
7.7
作者：
Gómez-Valadés AG;Méndez-Lucas A;Vidal-Alabró A;Blasco FX;Chillon M;Bartrons R;Bermúdez J;Perales JC
通讯作者：
Perales JC
影响因子：
64.5
作者：
Lin YY;Lu JY;Zhang J;Walter W;Dang W;Wan J;Tao SC;Qian J;Zhao Y;Boeke JD;Berger SL;Zhu H
通讯作者：
Zhu H
影响因子：
29
作者：
Burgess, Shawn C.;He, TianTeng;Magnuson, Mark A.
通讯作者：
Magnuson, Mark A.