Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene.
Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.
Rosen
H
H
Department of Molecular Virology, Faculty of Medicine, Hebrew University, 91120 Jerusalem, Israel.
Reshef
A
A
Maeda
N
N
Lippoldt
A
A
Shpizen
S
S
Triger
L
L
Eggertsen
G
G
Björkhem
I
I
Leitersdorf
E
E
D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism; D002338:Carotenoids / Q000097:blood; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000097:blood*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D005243:Feces / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D018390:Gene Targeting / Q000379:methods; D006888:Hydroxycholesterols / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000502:physiology; D013261:Sterols / Q000032:analysis; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014815:Vitamins / Q000097:blood; D019294:Xanthomatosis, Cerebrotendinous / Q000201:enzymology*
D001647:Bile Acids and Salts; D006888:Hydroxycholesterols; D013261:Sterols; D014815:Vitamins; D014807:Vitamin D; D002338:Carotenoids; C097949:1,25-dihydroxyvitamin D; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse