TY - JOUR
T1 - Hair growth defects in insig-deficient mice caused by cholesterol precursor accumulation and reversed by simvastatin
AU - Evers, Bret M.
AU - Farooqi, Midhat S.
AU - Shelton, John M.
AU - Richardson, James A.
AU - Goldstein, Joseph L.
AU - Brown, Michael S.
AU - Liang, Guosheng
N1 - Funding Information:
We thank the following colleagues for invaluable assistance: Fang Xu and Jonathan Cohen (GC-MS measurements), Jesse Morris (histological sections), and Monica Mendoza and Isis Soto (animal studies). We also thank Dr Paul Bergstresser for critical review of the paper. This research was supported by grants from The Hartwell Foundation, National Institutes of Health (HL-20948), and Perot Family Foundation. Bret M. Evers and Midhat S. Farooqi were supported by Medical Scientist Training Grant GM08014.
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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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U2 - 10.1038/jid.2009.442
DO - 10.1038/jid.2009.442
M3 - Article
C2 - 20090767
AN - SCOPUS:77951092696
SN - 0022-202X
VL - 130
SP - 1237
EP - 1248
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -