REGULATION OF FATTY-ACID SYNTHASE GENE-EXPRESSION - AN APPROACH FOR REDUCING FAT ACCUMULATION
REGULATION OF FATTY-ACID SYNTHASE GENE-EXPRESSION - AN APPROACH FOR REDUCING FAT ACCUMULATION
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DOI：
10.2527/1993.7171957x
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发表时间：
1993-07-01
影响因子：
3.3
通讯作者：
CLARKE, SD
中科院分区：
文献类型：
--
作者：
CLARKE, SD
脂肪酸合成酶（Fatty acid synthase， FAS）是脂肪酸生物合成途径的最后一步。FAS的组织浓度受许多激素和饮食因素的影响，是组织通过新生途径合成脂肪酸的最大能力的关键决定因素。已克隆出禽和大鼠FAS转录本的完整核苷酸序列。此外，从猪肝cDNA文库中分离出一个1.5 kb的cDNA，该cDNA代表猪FAS蛋白的硫酯酶结构域和转录物的整个3'-未翻译区。利用这些FAS cDNA工具，在大多数组织中发现了FAS mRNA转录物，包括脂肪、肝脏、肺、脑、肾和小肠。此外，组织中FAS mRNA的丰度决定了FAS蛋白的合成速度；最终是FAS蛋白的组织含量。在肝脏中，FAS基因转录率决定了FAS mRNA的水平，而脂肪组织中FAS mRNA的含量似乎是由影响基因转录和mRNA稳定性的因素决定的。FAS mRNA丰度的适应性变化似乎主要发生在肝脏和脂肪组织中，而FAS在其他组织类型中的表达则不受营养和激素操纵的影响。这篇综述提出了一个概念，即可以利用FAS基因表达的组织特异性适应来开发FAS基因表达的组织特异性抑制剂，从而通过新生生物合成途径降低组织脂肪积累的能力。这个概念的本质是可以确定FAS的特异性转录抑制剂，这些抑制剂会抑制FAS基因的转录，从而降低肝脏或脂肪组织重新生成脂肪的能力。被称为“靶向基因抑制剂测定”的测定可以适应于解决可能影响基因转录或mRNA稳定性的试剂。与酶活性抑制剂不同，这种基因表达抑制剂具有组织特异性的优势。显然，这种方法需要对控制肝脏或脂肪FAS表达的机制有详细的了解。因此，本综述的目标是提供这些监管事件的概述。
Fatty acid synthase (FAS) catalyzes the last step in the fatty acid biosynthetic pathway. The tissue concentration of FAS, which is affected by a number of hormonal and dietary factors, is a key determinant for the maximal capacity of a tissue to synthesize fatty acids by the de novo pathway. The complete nucleotide sequence of the avian and rat FAS transcripts has been cloned. In addition, a 1.5-kb cDNA that represents the thioesterase domain of the pig FAS protein plus the entire 3'-untranslated region of the transcript was isolated from a porcine liver cDNA library. Using these FAS cDNA tools, FAS mRNA transcripts have been found in most tissues, including adipose, liver, lung, brain, kidney, and small intestine. Moreover, the abundance of FAS mRNA in a tissue determines the rate of FAS protein synthesis; and ultimately the tissue content of FAS protein. In the liver, the rate of FAS gene transcription dictates the level of FAS mRNA, whereas the FAS mRNA content of adipose tissue seems to be determined by factors that affect gene transcription and mRNA stability. Adaptive changes in the abundance of FAS mRNA seem to occur primarily in hepatic and adipose tissues, whereas FAS expression in other tissue types is resistant to nutritional and hormonal manipulations. This review presents the concept that the tissue-specific adaptation in FAS gene expression can be exploited to develop a tissue-specific inhibitor of FAS gene expression and, hence, reduce the tissue capacity for fat accretion through the de novo biosynthetic pathway. The essence of the concept is that specific transcriptional inhibitors of FAS can be identified that will suppress the transcription of the FAS gene and, hence, decrease the hepatic or adipose tissue capacity for de novo lipogenesis. The assay termed ''targeted gene inhibitor assay'' can be adapted to address agents that may affect either gene transcription or mRNA stability. Unlike inhibitors of enzyme activity, such gene expression inhibitors provide an advantage of tissue specificity. Obviously, such an approach requires a detailed understanding of the mechanisms that govern the expression of liver or adipose FAS. Thus, it is the goal of this review to provide an overview of these regulatory events.