Hair growth defects in Insig-deficient mice caused by cholesterol precursor accumulation and reversed by simvastatin.
Hair growth defects in Insig-deficient mice caused by cholesterol precursor accumulation and reversed by simvastatin.
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DOI：
10.1038/jid.2009.442
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发表时间：
2010-05
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影响因子：
--
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中科院分区：
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Insig-1和Insig-2是两种密切相关的蛋白质，对胆固醇生物合成的反馈抑制至关重要。在这里，我们表征了一系列表皮特异性Insig双敲除（Epi-Insig-DKO）小鼠，其在表皮中缺乏两种Insig。在出生时，Epi-Insig-DKO小鼠与对照同窝小鼠无法区分，但此后它们未能茁壮成长并在6周龄前死亡。到14日龄时，100%的Epi-Insig-DKO小鼠表现出毛发生长缺陷沿着其他皮肤异常，包括角化过度。Epi-Insig-DKO小鼠的毛囊在出生后第7天正常发育，但它们未能进展到后期阶段，因此表现出出生后毛发周期的缺陷。Insig缺乏引起皮肤中胆固醇前体的显著积聚，与3-羟基-3-甲基戊二酰辅酶A还原酶蛋白的显著增加相关。用辛伐他汀（一种还原酶抑制剂）局部治疗Epi-Insig-DKO小鼠，减少了皮肤中的甾醇前体，并纠正了毛发和皮肤缺陷。我们的结论是，皮肤中Insig缺乏会导致胆固醇前体的积累，这会损害正常的毛发发育。这些发现对几种人类遗传性疾病有意义，这些疾病中胆固醇生物合成酶的突变导致固醇前体的积累和多种皮肤异常。
Insig-1 and Insig-2, two closely related proteins, are essential for feedback inhibition of cholesterol biosynthesis. Here, we characterized a line of epidermal-specific, Insig-double knockout (Epi-Insig-DKO) mice lacking both Insigs in epidermis. At birth, Epi-Insig-DKO mice were indistinguishable from control littermates, but thereafter they failed to thrive and died before 6 weeks of age. By 14 days of age, 100% of Epi-Insig-DKO mice exhibited defects in hair growth along with other skin abnormalities, including hyperkeratosis. Hair follicles in Epi-Insig-DKO mice developed normally through postnatal day 7, but they failed to progress to later stages and thus exhibited defects in postnatal hair cycling. Insig deficiency caused a marked buildup of cholesterol precursors in skin associated with a marked increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase protein. Topical treatment of Epi-Insig-DKO mice with simvastatin, an inhibitor of reductase, reduced sterol precursors in skin and corrected the hair and skin defects. We conclude that Insig deficiency in skin causes accumulation of cholesterol precursors, and this impairs normal hair development. These findings have implications for several human genetic diseases in which mutations in cholesterol biosynthetic enzymes lead to accumulation of sterol precursors and multiple cutaneous abnormalities.
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DOI：
10.1083/jcb.200510002
发表时间：
2006-01-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Wang X;Bolotin D;Chu DH;Polak L;Williams T;Fuchs E
通讯作者：
Fuchs E
影响因子：
2.7
作者：
Chiang, C;Swan, RZ;Dlugosz, AA
通讯作者：
Dlugosz, AA
影响因子：
9.2
作者：
St-Jacques, B;Dassule, HR;McMahon, AP
通讯作者：
McMahon, AP
影响因子：
15.9
作者：
Engelking, Luke J.;Evers, Bret M.;Liang, Guosheng
通讯作者：
Liang, Guosheng
影响因子：
30.8
作者：
Liu, XY;Dangel, AW;Herman, GE
通讯作者：
Herman, GE