Matsuzaka Takashi, Shimano Hitoshi, Yahagi Naoya, Yoshikawa Tomohiro, Amemiya-Kudo Michiyo, Hasty Alyssa H, Okazaki Hiroaki, Tamura Yoshiaki, Iizuka Yoko, Ohashi Ken, Osuga Jun-Ichi, Takahashi Akimitsu, Yato Shigeru, Sone Hirohito, Ishibashi Shun, Yamada Nobuhiro
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
J Lipid Res. 2002 Jun;43(6):911-20.
The mammalian enzyme involved in the final elongation of de novo fatty acid biosynthesis following the building of fatty acids to 16 carbons by fatty acid synthase has yet to be identified. In the process of searching for genes activated by sterol regulatory element-binding protein 1 (SREBP-1) by using DNA microarray, we identified and characterized a murine cDNA clone that is highly similar to a fatty acyl-CoA elongase gene family such as Cig30, Sscs, and yeast ELOs. Studies on the cells overexpressing the full-length cDNA indicate that the encoded protein, designated fatty acyl-CoA elongase (FACE), has a FACE activity specific for long-chains; C12-C16 saturated- and monosaturated-fatty acids. Hepatic expression of this identified gene was consistently activated in the livers of transgenic mice overexpressing nuclear SREBP-1a, -1c, or -2. FACE mRNA levels are markedly induced in a refed state after fasting in the liver and adipose tissue. This refeeding response is significantly reduced in SREBP-1 deficient mice. Dietary PUFAs caused a profound suppression of this gene expression, which could be restored by SREBP-1c overexpression. Hepatic FACE expression was also highly up-regulated in leptin-deficient ob/ob mice. Hepatic FACE mRNA was markedly increased by administration of a pharmacological agonist of liver X-activated receptor (LXR), a dominant activator for SREBP-1c expression. These data indicated that this elongase is a new member of mammalian lipogenic enzymes regulated by SREBP-1, playing an important role in de novo synthesis of long-chain saturated and monosaturated fatty acids in conjunction with fatty acid synthase and stearoyl-CoA desaturase.
在脂肪酸合酶将脂肪酸合成到16个碳原子之后，参与从头脂肪酸生物合成最终延伸过程的哺乳动物酶尚未被鉴定出来。在利用DNA微阵列寻找由固醇调节元件结合蛋白1（SREBP-1）激活的基因的过程中，我们鉴定并表征了一个小鼠cDNA克隆，它与脂肪酸酰基辅酶A延长酶基因家族（如Cig30、Sscs和酵母ELOs）高度相似。对过表达全长cDNA的细胞进行的研究表明，编码的蛋白质被命名为脂肪酸酰基辅酶A延长酶（FACE），具有对长链（C12 - C16饱和及单不饱和脂肪酸）特异的FACE活性。在过表达核SREBP-1a、-1c或-2的转基因小鼠肝脏中，该鉴定基因的肝脏表达持续被激活。禁食后的再喂食状态下，肝脏和脂肪组织中的FACE mRNA水平显著诱导。在SREBP-1缺陷小鼠中，这种再喂食反应显著降低。膳食多不饱和脂肪酸导致该基因表达受到深度抑制，而SREBP-1c的过表达可恢复这种抑制。在瘦素缺陷的ob/ob小鼠中，肝脏FACE表达也高度上调。肝脏X激活受体（LXR）的药理学激动剂（SREBP-1c表达的主要激活剂）给药后，肝脏FACE mRNA显著增加。这些数据表明，这种延长酶是受SREBP-1调节的哺乳动物脂肪生成酶的新成员，与脂肪酸合酶和硬脂酰辅酶A去饱和酶一起在长链饱和及单不饱和脂肪酸的从头合成中发挥重要作用。
