TY - JOUR
T1 - Disruption of cholesterol 7α-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation
AU - Ishibashi, Shun
AU - Schwarz, Margrit
AU - Frykman, Philip K.
AU - Herz, Joachim
AU - Russell, David W.
PY - 1996
Y1 - 1996
N2 - Mice deficient in cholesterol 7α-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, were constructed by targeted disruption of the Cyp7 gene. The introduced mutation removed exons 3-5 of the gene and gave rise to a null allele that encoded no immunoreactive or enzymatically active protein. Heterozygous carriers of the disrupted gene (Cyp7(+/-)) were phenotypically normal. Homozygous animals (Cyp7(-/-)) appeared normal at birth, but died within the first 18 days of life. Approximately 40% of the animals died between postnatal days 1 and 4 and 45% between days 11 and 18. The addition of vitamins to the water of nursing mothers prevented deaths in the early period, whereas the addition of cholic acid to chow prevented deaths in the later period. Newborn Cyp7(-/-) mice whose mothers were maintained on unsupplemented chow failed to gain weight at a normal rate and developed oily coats, hyperkeratosis, and apparent vision defects. These symptoms waned at 3 weeks of life, and their disappearance was accompanied by a marked increase in survival. In the accompanying study, the induction of an alternate pathway of bile acid biosynthesis is shown to underlie this unusual time course (Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden, H. J., Zerwekh, J. E., Bjorkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol. Chem. 271, 18024-18031). We conclude that cholesterol 7α-hydroxylase is an essential enzyme for normal postnatal development.
AB - Mice deficient in cholesterol 7α-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, were constructed by targeted disruption of the Cyp7 gene. The introduced mutation removed exons 3-5 of the gene and gave rise to a null allele that encoded no immunoreactive or enzymatically active protein. Heterozygous carriers of the disrupted gene (Cyp7(+/-)) were phenotypically normal. Homozygous animals (Cyp7(-/-)) appeared normal at birth, but died within the first 18 days of life. Approximately 40% of the animals died between postnatal days 1 and 4 and 45% between days 11 and 18. The addition of vitamins to the water of nursing mothers prevented deaths in the early period, whereas the addition of cholic acid to chow prevented deaths in the later period. Newborn Cyp7(-/-) mice whose mothers were maintained on unsupplemented chow failed to gain weight at a normal rate and developed oily coats, hyperkeratosis, and apparent vision defects. These symptoms waned at 3 weeks of life, and their disappearance was accompanied by a marked increase in survival. In the accompanying study, the induction of an alternate pathway of bile acid biosynthesis is shown to underlie this unusual time course (Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden, H. J., Zerwekh, J. E., Bjorkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol. Chem. 271, 18024-18031). We conclude that cholesterol 7α-hydroxylase is an essential enzyme for normal postnatal development.
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U2 - 10.1074/jbc.271.30.18017
DO - 10.1074/jbc.271.30.18017
M3 - Article
C2 - 8663429
AN - SCOPUS:0029666289
SN - 0021-9258
VL - 271
SP - 18017
EP - 18023
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 30
ER -