PMID- 10377398
OWN - NLM
STAT- MEDLINE
DCOM- 19990719
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 13
DP  - 1999 Jun 22
TI  - cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis
      in the brain.
PG  - 7238-43
AB  - The turnover of cholesterol in the brain is thought to occur via conversion of
      excess cholesterol into 24S-hydroxycholesterol, an oxysterol that is readily
      secreted from the central nervous system into the plasma. To gain molecular
      insight into this pathway of cholesterol metabolism, we used expression cloning
      to isolate cDNAs that encode murine and human cholesterol 24-hydroxylases. DNA
      sequence analysis indicates that both proteins are localized to the endoplasmic
      reticulum, share 95% identity, and represent a new cytochrome P450 subfamily
      (CYP46). When transfected into cultured cells, the cDNAs produce an enzymatic
      activity that converts cholesterol into 24S-hydroxycholesterol, and to a lesser
      extent, 25-hydroxycholesterol. The cholesterol 24-hydroxylase gene contains 15
      exons and is located on human chromosome 14q32.1. Cholesterol 24-hydroxylase is
      expressed predominantly in the brain as judged by RNA and protein blotting. In
      situ mRNA hybridization and immunohistochemistry localize the expression of this 
      P450 to neurons in multiple subregions of the brain. The concentrations of
      24S-hydroxycholesterol in serum are low in newborn mice, reach a peak between
      postnatal days 12 and 15, and thereafter decline to baseline levels. In contrast,
      cholesterol 24-hydroxylase protein is first detected in the brain of mice at
      birth and continues to accumulate with age. We conclude that the cloned cDNAs
      encode cholesterol 24-hydroxylases that synthesize oxysterols in neurons of the
      brain and that secretion of 24S-hydroxycholesterol from this tissue in the mouse 
      is developmentally regulated.
FAU - Lund, E G
AU  - Lund EG
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical
      Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9046, USA.
FAU - Guileyardo, J M
AU  - Guileyardo JM
FAU - Russell, D W
AU  - Russell DW
LA  - eng
SI  - GENBANK/AF094479
SI  - GENBANK/AF094480
GR  - P01 HL020948/HL/NHLBI NIH HHS/United States
GR  - HL 20948/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA, Complementary)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 1.14.- (Steroid Hydroxylases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Brain/*metabolism
MH  - Cholesterol/*metabolism
MH  - Cloning, Molecular
MH  - Cytochrome P-450 Enzyme System/genetics
MH  - DNA, Complementary/genetics/isolation & purification
MH  - Homeostasis
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Organ Specificity
MH  - Sequence Alignment
MH  - Steroid Hydroxylases/*genetics/metabolism
PMC - PMC22064
EDAT- 1999/06/23 00:00
MHDA- 1999/06/23 00:01
CRDT- 1999/06/23 00:00
PHST- 1999/06/23 00:00 [pubmed]
PHST- 1999/06/23 00:01 [medline]
PHST- 1999/06/23 00:00 [entrez]
AID - 10.1073/pnas.96.13.7238 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7238-43. doi:
      10.1073/pnas.96.13.7238.