Metabolism of 27-, 25- and 24-hydroxycholesterol in rat glial cells and neurons.
The metabolism of 27-, 25- and 24-hydroxycholesterol in cultures of rat astrocytes, Schwann cells and neurons was studied. 27- and 25-Hydroxycholesterol, but not 24-hydroxycholesterol, underwent 7 alpha-hydroxylation with subsequent oxidation to 7 alpha-hydroxy-3-oxo-delta 4 steroids in all three cell types. When cells were incubated for 24 h with 0.28 nmol of 27-hydroxycholesterol in 10 ml of medium, the rates of conversion into 7 alpha-hydroxylated metabolites were 0.21, 0.12 and 0.02 nmol/24 h per 10(6) cells in the media of astrocytes, Schwann cells and neurons respectively. The corresponding values for 25-hydroxycholesterol were 0.26, 0.16 and 0.04. A minor fraction of 27-hydroxycholesterol and its 7 alpha-hydroxylated metabolites was oxidized to 3 beta-hydroxy-5-cholestenoic acid. 3 beta, 7 alpha-dihydroxy-5-cholestenoic acid and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid. In addition to the two hydroxycholesterols, other 3 beta-hydroxy-delta 4 steroids, dehydro-epiandrosterone, pregnenolone, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid underwent 7 alpha-hydroxylation. Competitive experiments did not distinguish between the presence of one or several 7 alpha-hydroxylases. In astrocyte incubations, 27-hydroxycholesterol also underwent 25-hydroxylation, and 12% of its metabolites carried a 25-hydroxy group. 25-Hydroxylation of added 24-hydroxycholesterol was also observed in the astrocyte incubations, as was the formation of 7 alpha, 25-dihydroxy-4-cholesten-3-one, 25-hydroxycholesterol and 7 alpha, 25-dihydroxycholesterol from endogenous precursor(s). Our study indicates that side-chain oxygenated cholesterol can undergo metabolic transformations that may be of importance for cholesterol homoeostasis in the brain.
Zhang
J
J
Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Akwa
Y
Y
el-Etr
M
M
Baulieu
E E
EE
Sjövall
J
J
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002783:Cholestenones / Q000032:analysis; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D002793:Cholic Acids / Q000378:metabolism; D005333:Fetus; D006888:Hydroxycholesterols / Q000378:metabolism*; D006900:Hydroxylation; D008861:Microsomes / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism; D013379:Substrate Specificity
C104752:7,25-dihydroxy-4-cholesten-3-one; D002783:Cholestenones; D002793:Cholic Acids; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; C014596:3 beta-hydroxy-delta 5-cholenic acid; C029435:3-hydroxy-5-cholestenoic acid; C076996:27-hydroxycholesterol; C007997:25-hydroxycholesterol; D002784:Cholesterol