Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene
Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene
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DOI：
10.1172/jci119746
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发表时间：
1997-10-15
影响因子：
15.9
通讯作者：
Horton, JD
中科院分区：
文献类型：
--
作者：
Shimano, H;Shimomura, I;Horton, JD
胆固醇的合成及其从血浆低密度脂蛋白的摄取受两种膜结合转录因子的调控，即甾醇调节元件结合蛋白-1和-2 （SREBP-1和SREBP-2）。在这里，我们使用同源重组技术产生了编码SREBP-1两种亚型的基因中断的小鼠，称为SREBP-1a和SREBP-1c。杂合子基因破坏小鼠表型正常，但50-85%的纯合子（-/-）小鼠在胚胎第11天在子宫内死亡，存活的-/-小鼠在出生时和一生中表现正常，肝脏不表达功能性SREBP-1， SREBP-2 mRNA水平上调1.5倍，肝核中成熟SREBP-2的数量增加2 - 3倍，先前的研究表明SREBP-2比SREBP-1c更有效。SREBP-1的主要肝脏亚型，激活编码胆固醇合成酶的基因转录。与此观察一致，SREBP-1 -/-动物表现出3-羟基-3-甲基戊二酰辅酶A合成酶和还原酶、法尼酯二磷酸合成酶和角鲨烯合成酶的mrna水平升高。[H-3]水掺入后，-/-小鼠肝脏中胆固醇合成量增加了3倍，肝脏胆固醇含量增加了50%，脂肪酸合成量减少。在-/-小鼠中，白色脂肪组织的数量没有明显减少，脂肪生成酶、脂肪细胞脂质结合蛋白、脂蛋白脂肪酶和瘦素的mrna水平正常。我们从这些研究中得出结论，SREBP-2可以取代SREBP-1调节小鼠肝脏中的胆固醇合成，并且相对于SREBP-1c， SREBP-2的更高的效率导致这些动物肝脏中胆固醇合成过量。
The synthesis of cholesterol and its uptake from plasma LDL are regulated by two membrane-bound transcription factors, designated sterol regulatory element binding protein-1 and -2 (SREBP-1 and SREBP-2), Here, we used the technique of homologous recombination to generate mice with disruptions in the gene encoding the two isoforms of SREBP-1, termed SREBP-1a and SREBP-1c. Heterozygous gene-disrupted mice were phenotypically normal, but 50-85% of the homozygous (-/-) mice died in utero at embryonic day 11, The surviving -/- mice appeared normal at birth and throughout life, Their livers expressed no functional SREBP-1, There was a 1.5-fold upregulation of SREBP-2 at the level of mRNA and a two-to threefold increase in the amount of mature SREBP-2 in liver nuclei, Previous studies showed that SREBP-2 is much more potent than SREBP-1c, the predominant hepatic isoform of SREBP-1, in activating transcription of genes encoding enzymes of cholesterol synthesis, Consistent with this observation, the SREBP-1 -/- animals manifested elevated levels of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, farnesyl diphosphate synthase, and squalene synthase. Cholesterol synthesis, as measured by the incorporation of [H-3]water, was elevated threefold in livers of the -/- mice, and hepatic cholesterol content was increased by 50%, Fatty acid synthesis was decreased in livers of the -/- mice. The amount of white adipose tissue was not significantly decreased, and the levels of mRNAs for lipogenic enzymes, adipocyte lipid binding protein, lipoprotein lipase, and leptin were normal in the -/- mice, We conclude from these studies that SREBP-2 can replace SREBP-1 in regulating cholesterol synthesis in livers of mice and that the higher potency of SREBP-2, relative to SREBP-1c leads to excessive hepatic cholesterol synthesis in these animals.