Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal
Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal
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DOI：
10.1073/pnas.0505714102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Wakil, SJ
中科院分区：
文献类型：
--
作者：
Abu-Elheiga, L;Matzuk, MM;Wakil, SJ
乙酰辅酶A羧化酶（ACC 1和ACC 2）催化乙酰辅酶A羧化形成丙二酰辅酶A，丙二酰辅酶A是一种中间代谢产物，在脂肪酸代谢的调节中起关键作用。我们以前报道过，ACC 2基因敲除小鼠是可行的，并且ACC 2通过抑制脂肪酸-酰基穿梭系统的线粒体组分肉毒碱棕榈酰转移酶1在调节脂肪酸氧化中起着重要作用。在此，我们使用基因靶向敲除ACC 1基因。杂合突变小鼠（Acc 1（+/-））具有正常的生育能力和寿命，并保持与野生型队列相似的体重。Acc 1（+/-）小鼠组织中ACC 1的mRNA水平是野生型的一半;然而，ACC 1的蛋白水平和总丙二酰辅酶A水平相似。此外，Acc 1（+/-）小鼠肝细胞与野生型肝细胞之间的乙酸盐掺入脂肪酸和脂肪酸氧化均无差异。与Acc 2（-/-）小鼠相反，交配后未检测到Acc 1（-/-）小鼠。杂合子的定时妊娠显示，Acc（-/-）胚胎在胚胎日（E）7.5时已经未发育，它们在E8.5时死亡，并在E11.5时完全吸收。我们先前对ACC 2敲除小鼠的研究结果和目前对ACC 1敲除小鼠的研究进一步证实了我们的假设，即丙二酰辅酶A存在于两个独立的库中，并且ACC 1和ACC 2在脂肪酸代谢中具有不同的作用。
Acetyl-CoA carboxylases (ACC1 and ACC2) catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a pivotal role in the regulation of fatty acid metabolism. We previously reported that ACC2 null mice are viable, and that ACC2 plays an important role in the regulation of fatty acid oxidation through the inhibition of carnitine palmitoyltransferase 1, a mitochondrial component of the fatty-acyl shuttle system. Herein, we used gene targeting to knock out the ACC1 gene. The heterozygous mutant mice (Acc1(+/-)) had normal fertility and lifespans and maintained a similar body weight to that of their wild-type cohorts. The mRNA level of ACC1 in the tissues of Acc1(+/-) mice was half that of the wild type; however, the protein level of ACC1 and the total malonyl-CoA level were similar. In addition, there was no difference in the acetate incorporation into fatty acids nor in the fatty acid oxidation between the hepatocytes of Acc1(+/-) mice and those of the wild type. In contrast to Acc2(-/-) mice, Acc1(-/-) mice were not detected after mating. Timed pregnancies of heterozygotes revealed that Acc(-/-) embryos are already undeveloped at embryonic day (E)7.5, they die by E8.5, and are completely resorbed at E11.5. Our previous results of the ACC2 knockout mice and current studies of ACC1 knockout mice further confirm our hypotheses that malonyl-CoA exists in two independent pools, and that ACC1 and ACC2 have distinct roles in fatty acid metabolism.