SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation
SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation
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DOI：
10.1101/gad.891301
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发表时间：
2001-05-15
影响因子：
10.5
通讯作者：
Shimomura, I
中科院分区：
文献类型：
--
作者：
Matsuda, M;Korn, BS;Shimomura, I
在肝脏中，胆固醇和脂肪酸的合成分别因胆固醇缺乏和胰岛素升高而增加。这种调节机制是适应胆固醇合成抑制剂(他汀类药物)和高热量饮食(胰岛素)的基础。在非肝细胞中，脂质的合成由类固醇调节元件结合蛋白(SREBPs)控制，SREBPs是一种膜结合转录因子，其活性区域被蛋白水解性释放进入细胞核，激活参与胆固醇和脂肪酸合成和吸收的基因。SCAP(SREBP裂解激活蛋白)是一种受类固醇调节的护卫蛋白，它将SREBPs从内质网的合成部位运送到高尔基体的裂解部位。在这里，我们通过可诱导的Cre重组酶介导的基因组重组，在小鼠肝脏中产生了SCAP的条件性缺陷。由于编码多种生物合成酶的mRNAs减少，SCAP缺陷小鼠肝脏中胆固醇和脂肪酸合成的基础速率降低了80%。此外，在胆固醇合成抑制剂产生的胆固醇缺乏和禁食-再喂养方案产生的胰岛素升高的反应中，这些mRNAs未能正常增加。这些数据提供了体内证据，表明在基础和适应条件下，SCAP和SREBPs是肝脏脂肪合成所必需的。
In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting-refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.