Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene
Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene
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DOI：
10.1073/pnas.201524598
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发表时间：
2001-11-20
影响因子：
11.1
通讯作者：
Horton, JD
中科院分区：
文献类型：
--
作者：
Yang, J;Goldstein, JL;Horton, JD
Site-1蛋白酶（S1P）切割膜结合的固醇调节元件结合蛋白（srebp），允许其转录刺激结构域转移到细胞核，在那里它们激活控制脂质合成的基因。SIP是降脂药物的潜在靶点，但阻断S1P对动物的影响尚不清楚。在这里，我们破坏了小鼠的S1P基因。S1P的纯合子种系破坏具有胚胎致死性。为了在肝脏中诱导破坏该基因，我们在ifn诱导的MX1启动子的控制下，培养了一个固定的S1P等位基因的纯合子和一个编码Cre重组酶的转基因的杂合子。当IFN产生时，肝脏中70-90%的S1P等位基因失活，SIP mRNA和蛋白减少。核SREBP下降，SREBP靶基因的mrna也下降。肝细胞的胆固醇和脂肪酸生物合成下降了75%。低密度脂蛋白（LDL）受体mRNA下降了50%，血浆中i -125标记LDL的清除率也下降了50%，但血浆胆固醇下降，表明LDL的产生减少了。这些数据提高了SIP抑制剂可能是有效的降脂剂的可能性，但它们表明需要几乎完全的抑制。
Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. SIP is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90% of S1P alleles in liver were inactivated, and SIP mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of I-125-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that SIP inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.