PCK1 and PCK2 as candidate diabetes and obesity genes
PCK1 and PCK2 as candidate diabetes and obesity genes
复制标题
DOI：
10.1007/s12013-007-0025-6
复制
发表时间：
2007-01-01
影响因子：
2.6
通讯作者：
Forest, Claude
中科院分区：
文献类型：
--
作者：
Beale, Elmus G.;Harvey, Brandy J.;Forest, Claude
PCK 1基因（啮齿类动物中的Pck 1）编码磷酸烯醇丙酮酸羧激酶（PEPCK-C）的胞浆同工酶，PEPCK-C因其在肝脏和肾脏中作为致炎酶的功能而闻名。涉及全身和组织特异性Pck 1敲除以及PEPCK-C组织特异性过表达的小鼠研究已导致2型糖尿病以及几种令人惊讶的表型，包括肥胖、脂肪代谢障碍、脂肪肝和死亡。这些表型不仅是由代谢产物发生的扰动引起的，而且也是由PEPCK-C的两种其他代谢功能的扰动引起的：（1）通过去除过量的草酰乙酸来维持通过克雷布斯循环的代谢通量的分解作用，和（2）产生甘油-3-磷酸作为脂肪酸酯化成甘油三酯的前体的甘油生成作用。PEPCK-C催化草酰乙酸+ GTP转化为磷酸烯醇丙酮酸+ GDP + CO2。正是这种简单反应的组织特异性导致了上面列出的各种表型。简言之：（1）小鼠肝脏中PEPCK-C的7倍过表达导致过量的葡萄糖产生。(2)Pck 1整体敲除的小鼠在出生后2-3天内死亡，不是因为低血糖，而是可能因为克雷布斯循环在没有退化的情况下减慢到正常的约10%。(3)具有肝脏特异性基因敲除的小鼠无法从克雷布斯循环中去除草酰乙酸，这导致禁食后的脂肪肝。(4)脂肪特异性敲除Pck 1导致一部分小鼠由于甘油生成丧失而发生脂肪营养不良，从而减少脂肪酸再酯化。(5)最后，脂肪组织中PEPCK-C的失调过度表达增加脂肪酸再酯化，导致肥胖。小鼠中这些不同的实验表型使我们推测，人类中由两种PEPCK基因PCK 1和PCK 2编码的PEPCK同工酶的异常产生可能具有类似的结果（Beale，E. G.等（2004）。Trends in Endocrinology and Metabolism，15，129-135）。本次审查的目的是进一步探讨这些可能性。
The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities.