Valera A, Pelegrin M, Asins G, Fillat C, Sabater J, Pujol A, Hegardt F G, Bosch F
Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Autonomous University of Barcelona, Bellaterra, Spain.
J Biol Chem. 1994 Mar 4;269(9):6267-70.
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) is a key enzyme in the ketone body pathway. To determine its role in the regulation of liver ketogenesis, transgenic mice expressing a P-enolpyruvate carboxykinase/HMG-CoA synthase chimeric gene have been obtained. An increase in the concentration of mitochondrial HMG-CoA synthase mRNA was detected in these mice, which was associated with a 3-fold increase in HMG-CoA synthase activity in liver mitochondrial extracts. Transgenic mice were normoglycemic and had normal levels of plasma triglycerides and lower free fatty acids. However, the plasma concentration of ketone bodies was about three times higher in transgenic mice than in control animals. Hepatocytes in primary culture from transgenic mice expressed the chimeric gene in a regulated manner and showed a 3-fold increase in beta-hydroxybutyrate and acetoacetate concentrations in the medium. This animal model thus shows that the overexpression of mitochondrial HMG-CoA synthase causes ketone body overproduction, suggesting that this enzyme may be a regulatory step in liver ketogenesis.
线粒体3-羟基-3-甲基戊二酰辅酶A合酶（HMG-CoA合酶）是酮体生成途径中的关键酶。为了确定其在肝脏生酮调节中的作用，已获得表达磷酸烯醇式丙酮酸羧激酶/HMG-CoA合酶嵌合基因的转基因小鼠。在这些小鼠中检测到线粒体HMG-CoA合酶mRNA浓度增加，这与肝脏线粒体提取物中HMG-CoA合酶活性增加3倍相关。转基因小鼠血糖正常，血浆甘油三酯水平正常，游离脂肪酸水平较低。然而，转基因小鼠血浆中酮体浓度约为对照动物的三倍。来自转基因小鼠的原代培养肝细胞以受调控的方式表达嵌合基因，并且培养基中β-羟基丁酸酯和乙酰乙酸酯浓度增加了3倍。因此，这个动物模型表明线粒体HMG-CoA合酶的过表达导致酮体过量产生，这表明该酶可能是肝脏生酮过程中的一个调节步骤。
