Fatty acid synthesis is essential in embryonic development:: Fatty acid synthase null mutants and most of the heterozygotes die in utero
Fatty acid synthesis is essential in embryonic development:: Fatty acid synthase null mutants and most of the heterozygotes die in utero
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DOI：
10.1073/pnas.0931394100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Wakil, SJ
中科院分区：
文献类型：
--
作者：
Chirala, SS;Chang, H;Wakil, SJ
在包括人类在内的动物中，长链饱和脂肪酸的来源是由脂肪酸合成酶（FAS）、摄入的食物或两者介导的从头合成。为了了解重新合成脂肪酸的重要性，我们制造了FAS敲除小鼠。杂合子FAS突变体（Fasn(+/-)）表面上是正常的。Fasn（+/-）小鼠FAS mRNA水平和FAS活性分别比WT小鼠低约50%和35%；因此，FAS水平受到基因剂量的影响。当Fasn（+/-）突变小鼠杂交时，不产生Fasn（-/-）突变小鼠；此外，获得的Fasn（+/-）后代的数量比孟德尔遗传预测的少70%，表明部分单倍体不足。即使父母一方是WT，估计杂合后代的损失为60%。这种Fasn（+/-）幼崽的丢失似乎是菌株特异性的，并且随着杂合雌性产生更多的幼崽而变得更加明显。大多数Fasn（-/-）突变体胚胎在着床前死亡，Fasn（+/-）突变体胚胎在发育的不同阶段死亡。给繁殖者喂食富含饱和脂肪酸的食物并不能防止同源或杂合子的丢失。这些观察结果对于考虑旨在抑制FAS活性的药物的致畸后果非常重要，以减少肥胖或癌组织的生长。
in animals, including humans, the source of long-chain saturated fatty acids is de novo synthesis, which is mediated by fatty acid synthase (FAS), ingested food, or both. To understand the importance of de novo fatty acid synthesis, we generated FAS knockout mice. The heterozygous FAS mutants (Fasn(+/-)) are ostensibly normal. In Fasn(+/-) mice the levels of FAS mRNA and the FAS activity are approximate to50% and 35% lower, respectively, than those of WT mice; hence, FAS levels are affected by gene dosage. When the Fasn(+/-) mutant mice were interbred, Fasn(-/-) mice were not produced; thus, FAS is essential during embryonic development, Furthermore, the number of Fasn(+/-) progeny obtained was 70% less than predicted by Mendelian inheritance, indicating partial haploid insufficiency. Even when one of the parents was WT, the estimated loss of heterozygous progeny was 60%. This loss of Fasn(+/-) pups appeared to be strain-specific and became more pronounced as the heterozygous females produced more litters. Most of the Fasn(-/-) mutant embryos died before implantation and the Fasn(+/-) embryos died at various stages of their development. Feeding the breeders a diet rich in saturated fatty acids did not prevent the loss of homo- or heterozygotes. These observations are very important in considering teratogenic consequences of drugs aimed at inhibiting FAS activity, to reduce either obesity or the growth of cancerous tissues.