Removal of cholesterol from extrahepatic sources by oxidative mechanisms

Current Opinion in Lipidology

Volumn 10, Issue 2, 1999, Pages 161-165

  Björkhem, Ingemar ^a   Diczfalusy, Ulf ^a   Lütjohann, Dieter ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

BILE ACID; CHOLESTEROL; CYTOCHROME P450;

AEROBIC METABOLISM; BILE ACID SYNTHESIS; BLOOD BRAIN BARRIER; BRAIN METABOLISM; CHOLESTEROL METABOLISM; HOMEOSTASIS; LIVER METABOLISM; ORGAN DISTRIBUTION; PRIORITY JOURNAL; SHORT SURVEY; TISSUE DISTRIBUTION;

BRAIN; CHOLESTEROL; HUMANS; LIPOPROTEINS, HDL; LIVER; LUNG; MACROPHAGES; MIXED FUNCTION OXYGENASES; MODELS, BIOLOGICAL; STEROID HYDROXYLASES;

EID: 0032892176     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-199904000-00010     Document Type: Short Survey

References (20)

1. Prinsen HMG, Post SM, Twisk J. Regulation of bile acid synthesis and the regulation of this synthesis. Curr Pharm Design 1997; 3:59-84. This is an excellent up-to-date review on the mechanism of bile acid synthesis and the regulation of this synthesis. It is emphasized that sterol 27-hydroxylase may be a new target for antiatherogenic therapy.
2. Björkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci U S A 1994; 91:8592-8596.
3. Lund E, Andersson O, Zhang J, Babiker A, Diczfalusy U, Ahlborg G, et al. Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans. Arterioscler Thromb Vasc Biol 1996; 16:208-212.
4. Babiker A, Andersson O, Lund E, Xiu RJ, Deeb S, Reshef A, et al. Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism J Biol Chem 1997, 272:26253-26261. It is shown that secretion of 27-oxygenated products by cultured macrophages as well as the ratio between the alcohol and the acid depends upon the total amount of enzyme, availability of substrate cholesterol and the presence of an acceptor for 27-hydroxycholesterol in the medium. With albumin acting as an acceptor, the major secreted product was cholestenoic acid and under such conditions secretion of 27-oxygenated products was higher than secretion of cholesterol. With HDL as acceptor, 27-hydroxycholesterol was the major product.
5. Reiss AB, Martin KO, Javitt NB, Martin DW, Grossi EA, Galloway AC. Sterol 27-hydroxylase: high level of activity in vascular endothelium J Lipid Res 1994; 35:1026-1030
6. Andersson S, Davis DL, Dahlbäck H, Jörnvall H, Russel DW. Cloning, structure and expression of the mitochondrial P-450 sterol 26-hydroxylase, a bile biosynthetic enzyme. J Biol Chem 1989; 264:8222-8229.
7. Lange Y, Ye J, Strebel F. Movement of 25-hydroxycholesterol from the plasma membrane to the rough endoplasmic reticulum in cultured hepatoma cells. J Lipid Res 1995; 36:1092-1097.
8. Pikuleva IA, Babiker A, Waterman MR, Björkhem I. Activities of recombinant human cytochrome P-450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways. J Biol Chem 1998; 273:18153-18160.
9. Westman J, Kallin B, Björkhem I, Nilsson J, Diczfalusy U. Sterol 27-hydroxylase and apo Al/phospholipid mediated efflux of cholesterol from cholesterol laden macrophages: evidence for an inverse relation betwen the two mechanisms. Arterioscler Thromb Vasc Biol 1998; 18:554-561.
10. Babiker A, Diczfalusy U. Transport of side-chain oxidized oxysterols in the human circulation. Biochim Biophys Acta 1998; 1392:333-339.
11. Setchell K, Schwarz M, O'Conell NC, Lund EG, Davies DL, Lathe R, et al. Identification of a new inborn error in bile acid biosynthesis: mutation of the oxysterol 7α-hydroxylase gene causing severe neonatal liver disease. J Clin Invest 1998; 102:1690-1703 This is a most interesting paper which describes for the first time a genetic defect in the oxysterol 7α-hydroxylase As a consequence of this defect the patient (a 10-week-old boy presenting with severe cholestasis, cirrhosis and liver synthetic failure) had extremely high concentrations of 27-hydroxy-cholesterol in the circulation (more than 4500 times the normal level). Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells
12. Crisby M, Nilsson J, Kostulas V, Björkhem I, Diczfalusy U Location of sterol 27-hydroxylase immunoreactivity in human atherosclerotic plaques. Biochim Biophys Acta 1997; 1344:278-285
13. Björkhem I, Muri-Boberg K. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In. The metabolic basis of inherited diseases. Scriver CR, Beaudet AL, Sly WS, Valee D (editors). New York, NY: McGraw Hill, 1994 pp. 2073-2100.
14. Fujiyama J, Kunyama M, Arima S, Shibata Y, Nagata K, Takenaga S, et al Atherogenic risk factors in CTX Clin Chim Acta 1991; 200:1-12
15. Rosen H, Reshef A, Maeda N, Lippoldt A, Shpizen S, Triger L, et al. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J Biol Chem 1998; 273 14805-14812. It is shown that a disruption of the sterol 27-hydroxylase gene in mice leads to markedly reduced bile acid synthesis but no accumulation of cholestanol or development of xanthomas as in CTX patients lacking the sterol 27-hydroxylase
16. Kushwaha RS, Guntupalli B, Rice KS, Carey KD, McGill HC. Effect of dietary cholesterol and fat on the expression of hepatic cholesterol 27-hydroxylase and other hepatic cholesterol-responsive genes in baboons. Arterioscler Thromb Vasc Biol 1995; 15:1404-1411.
17. Ercoli A, DeRuggieri P. The constitution of cerebrosterol, a hydroxysteroid isolated from horse brain Gazz Chim Ital 1953, 83:73-86.
18. Lütjohann D, Breuer O, Ahlborg G, Nennesmo I, Sidén Å, Diczfalusy U, Björkhem I. Cholesterol homeostasis in human brain: Evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 1996; 93:9799-9804.
19. Björkhem I, Lütjohann D, Diczfalusy U, Ståhle L, Ahlborg G, Wahren J. Cholesterol homeostasis in human brain Turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation J Lipid Res 1998, 39.1594-1600.
20. Björkhem I, Lutjohann D, Breuer O, Sakinis A, Wennmalm Å Importance of a novel oxidative mechanism for elimination of brain cholesterol. J Biol Chem 1997; 272:30178-30184 It is shown that the 24S-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats The results suggest that the 24S-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain.