Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin
Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin
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DOI：
10.1172/jci28988
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Liang, Guosheng
中科院分区：
文献类型：
--
作者：
Engelking, Luke J.;Evers, Bret M.;Liang, Guosheng
Insig-1和Insig-2是通过阻止SREBP的蛋白水解活化和通过增强HMG-CoA还原酶的降解来限制胆固醇生物合成途径的调节蛋白。在这里，我们创建了Insig-双敲除（Insig-DKO）小鼠，其对于Insig-1和Insig-2中的无效突变是纯合的。在发育18.5天后，96%的Insig-DKO胚胎在中线面部发育中存在缺陷，从腭裂（52%）到完全腭裂（44%）。中耳和内耳结构异常，但牙齿和骨骼正常。这些动物嗜睡且发育不良;它们在出生后1天内死亡。Insig-DKO胚胎的肝脏和头部过度产生甾醇，导致甾醇中间体的显著积累。用HMG-CoA还原酶抑制剂洛伐他汀治疗怀孕小鼠减少了Insig-DKO胚胎中的甾醇合成，并减少了前胆固醇中间体。这种治疗改善了裂面综合征，使54%的Insig-DKO小鼠具有正常的面部，只有7%具有裂面。我们的结论是，建立前胆固醇甾醇中间体干扰中线融合的面部结构在小鼠。这些发现对Smith-Lemli-Opitz综合征和其他人类畸形综合征的腭裂部分的发病机制有影响，其中胆固醇生物合成中催化步骤的酶突变产生甾醇中间体的积累。
Insig-1 and Insig-2 are regulatory proteins that restrict the cholesterol biosynthetic pathway by preventing proteolytic activation of SREBPs and by enhancing degradation of HMG-CoA reductase. Here, we created Insig-double-knockout (Insig-DKO) mice that are homozygous for null mutations in Insig-1 and Insig-2. After 18.5 days of development, 96% of Insig-DKO embryos had defects in midline facial development, ranging from cleft palate (52%) to complete cleft face (44%). Middle and inner ear structures were abnormal, but teeth and skeletons were normal. The animals were lethargic and runted; they died within 1 day of birth. The livers and heads of Insig-DKO embryos overproduced sterols, causing a marked buildup of sterol intermediates. Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates. This treatment ameliorated the clefting syndrome so that 54% of Insig-DKO mice had normal faces, and only 7% had cleft faces. We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice. These findings have implications for the pathogenesis of the cleft palate component of Smith-Lemli-Opitz syndrome and other human malformation syndromes in which mutations in enzymes catalyzing steps in cholesterol biosynthesis produce a buildup of sterol intermediates.