Novel oxysterols observed in tissues and fluids of AY9944-treated rats: A model for Smith-Lemli-Opitz syndrome

Journal of Lipid Research

Volumn 52, Issue 10, 2011, Pages 1810-1820

  Xu, Libin ^a   Liu, Wei ^a   Shefli, Lowell G ^b   Fliesler, Steven J ^a,c,d   Porter, Ned A ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VA WESTERN NEW YORK HEALTHCARE SYSTEM   (United States)

^c UNIVERSITY AT BUFFALO   (United States)

^d SUNY EYE INSTITUTE   (United States)

Author keywords

7 dehydrocholesterol; Cholesterol; Cholesterol biosynthesis; Lipids peroxidation

Indexed keywords

1,4 BIS(2 CHLOROBENZYLAMINOMETHYL)CYCLOHEXANE; 24 HYDROXY 7 DEHYDROCHOLESTEROL; 3BETA,5ALPHA DEHYDROCHOLEST 7 EN 6 ONE; 4ALPHA HYDROXY 7 DEHYDROCHOLESTEROL; 4BETA HYDROXY 7 DEHYDROCHOLESTEROL; 7 DEHYDROCHOLESTEROL; 7 OXOCHOLESTEROL; UNCLASSIFIED DRUG;

ANATOMICAL VARIATION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN; CONTROLLED STUDY; ENZYME ANALYSIS; ENZYME STRUCTURE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; LIVER; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RAT; SERUM; SMITH LEMLI OPITZ SYNDROME; TISSUE LEVEL;

ANIMALS; ANTICHOLESTEREMIC AGENTS; CHOLESTENONES; CHOLESTEROL; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DEHYDROCHOLESTEROLS; DISEASE MODELS, ANIMAL; HYDROXYCHOLESTEROLS; KETOCHOLESTEROLS; LIPID PEROXIDATION; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MICE; RATS; RATS, SPRAGUE-DAWLEY; SMITH-LEMLI-OPITZ SYNDROME; SPECTROPHOTOMETRY, ULTRAVIOLET; STEROLS; TRANS-1,4-BIS(2-CHLOROBENZAMINOMETHYL)CYCLOHEXANE DIHYDROCHLORIDE;

EID: 80053211271     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M018366     Document Type: Article

References (75)

1. Irons, M., E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta. 1993. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 341 : 1414.
2. Tint, G. S., M. Irons, E. R. Elias, A. K. Batta, R. Frieden, T. S. Chen, and G. Salen. 1994. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330 : 107-113.
3. Fitzky, B. U., F. F. Moebius, H. Asaoka, H. Waage-Baudet, L. Xu, G. Xu, N. Maeda, K. Kluckman, S. Hiller, H. Yu, et al. 2001. 7-Dehydrocholesterol- dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith- Lemli-Opitz/RSH syndrome. J. Clin. Invest. 108 : 905-915.
4. Krakowiak, P. A., N. A. Nwokoro, C. A. Wassif, K. P. Battaile, M. J. Nowaczyk, W. E. Connor, C. Maslen, R. D. Steiner, and F. D. Porter. 2000. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am. J. Med. Genet. 94 : 214-227.
5. Waterham, H. R. 2002. Inherited disorders of cholesterol biosynthesis. Clin. Genet. 61 : 393-403.
6. Sikora, D., K. Pettit-Kekel, J. Penfi eld, L. Merkens, and R. Steiner. 2006. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 140 : 1511-1518.
7. Porter, F. D., and G. E. Herman. 2011. Malformation syndromes caused by disorders of cholesterol synthesis. J. Lipid Res. 52 : 6-34.
8. Kelley, R. I., and R. C. Hennekam. 2000. The Smith-Lemli-Opitz syndrome. J. Med. Genet. 37 : 321-335.
9. Porter, F. D. 2003. Human malformation syndromes due to inborn errors of cholesterol synthesis. Curr. Opin. Pediatr. 15 : 607-613.
10. Bukelis, I., F. D. Porter, A. W. Zimmerman, and E. Tierney. 2007. Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am. J. Psychiatry. 164 : 1655-1661.
11. Charman, C. R., A. Ryan, R. M. Tyrrell, A. D. Pearse, C. F. Arlett, H. A. Kurwa, G. Shortland, and A. Anstey. 1998. Photosensitivity associated with the Smith-Lemli-Opitz syndrome. Br. J. Dermatol. 138 : 885-888.
12. Irons, M., E. R. Elias, G. S. Tint, G. Salen, R. Frieden, T. M. Buie, and M. Ampola. 1994. Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical fi ndings in four patients and treatment in one patient. Am. J. Med. Genet. 50 : 347-352.
13. Elias, E. R., M. B. Irons, A. D. Hurley, G. S. Tint, and G. Salen. 1997. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. Genet. 68 : 305-310.
14. Irons, M., E. R. Elias, D. Abuelo, M. J. Bull, C. L. Greene, V. P. Johnson, L. Keppen, C. Schanen, G. S. Tint, and G. Salen. 1997. Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am. J. Med. Genet. 68 : 311-314.
15. Starck, L., A. Lovgren-Sandblom, and I. Bjorkhem. 2002. Cholesterol treatment forever? The fi rst Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith- Lemli-Opitz syndrome. J. Intern. Med. 252 : 314-321.
16. Sikora, D. M., M. Ruggiero, K. Petit-Kekel, L. S. Merkens, W. E. Connor, and R. D. Steiner. 2004. Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J. Pediatr. 144 : 783-791.
17. Haas, D., S. F. Garbade, C. Vohwinkel, N. Muschol, F. K. Trefz, J. M. Penzien, J. Zschocke, G. F. Hoffmann, and P. Burgard. 2007. Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS). J. Inherit. Metab. Dis. 30 : 375-387.
18. Tierney, E., S. K. Conley, H. Goodwin, and F. D. Porter. 2010. Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. A. 152A : 91-95.
19. Xu, L., T. A. Davis, and N. A. Porter. 2009. Rate constants for peroxidation of polyunsaturated fatty acids and sterols in solution and in liposomes. J. Am. Chem. Soc. 131 : 13037-13044.
20. Xu, L., Z. Korade, and N. A. Porter. 2010. Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies. J. Am. Chem. Soc. 132 : 2222-2232.
21. Korade, Z., L. Xu, R. Shelton, and N. A. Porter. 2010. Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome. J. Lipid Res. 51 : 3259-3269.
22. Fliesler, S. J. 2010. Retinal degeneration in a rat model of Smith- Lemli-Opitz syndrome: thinking beyond cholesterol defi ciency. Adv. Exp. Med. Biol. 664 : 481-489.
23. Smith, L. L., and B. H. Johnson. 1989. Biological activities of oxysterols. Free Radic. Biol. Med. 7 : 285-332.
24. Brown, A. J., and W. Jessup. 1999. Oxysterols and atherosclerosis. Atherosclerosis. 142 : 1-28.
25. Schroepfer, G. J., Jr. 2000. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol. Rev. 80 : 361-554.
26. Javitt, N. B. 2007. Oxysterols: functional signifi cance in fetal development and the maintenance of normal retinal function. Curr. Opin. Lipidol. 18 : 283-288.
27. Javitt, N. B. 2008. Oxysterols: novel biologic roles for the 21st century. Steroids. 73 : 149-157.
28. Björkhem, I., A. Cedazo-Minguez, V. Leoni, and S. Meaney. 2009. Oxysterols and neurodegenerative diseases. Mol. Aspects Med. 30 : 171-179.
29. Brown, A. J., and W. Jessup. 2009. Oxysterols: sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis. Mol. Aspects Med. 30 : 111-122
30. Vejux, A., and G. Lizard. 2009. Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/ or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol. Aspects Med. 30 : 153-170.
31. Olkkonen, V. M., and R. Hynynen. 2009. Interactions of oxysterols with membranes and proteins. Mol. Aspects Med. 30 : 123-133.
32. Xu, L., Z. Korade, D. A. Rosado, W. Liu, C. R. Lamberson, and N. A. Porter. 2011. An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome. J. Lipid Res. 52 : 1222-1233.
33. Chappel, C., D. Dubuc, D. Dvornik, M. Givner, L. Humber, M. Kraml, K. Voith, and R. Gaudry. 1964. An inhibitor of cholesterol biosynthesis. Nature 201 : 497-498.
34. Givner, M. L., and D. Dvornik. 1965. Agents affecting lipid metabolism-XV. Biochemical studies with the cholesterol biosynthesis inhibitor AY-9944 in young and mature rats. Biochem. Pharmacol. 14 : 611-619.
35. Kolf-Clauw, M., F. Chevy, C. Wolf, B. Siliart, D. Citadelle, and C. Roux. 1996. Inhibition of 7-dehydrocholesterol reductase by the teratogen AY9944: a rat model for Smith-Lemli-Opitz syndrome. Teratology. 54 : 115-125.
36. Wolf, C., F. Chevy, J. Pham, M. Kolf-Clauw, D. Citadelle, N. Mulliez, and C. Roux. 1996. Changes in serum sterols of rats treated with 7-dehydrocholesterol-delta 7-reductase inhibitors: comparison to levels in humans with Smith-Lemli-Opitz syndrome. J. Lipid Res. 37 : 1325-1333.
37. Kolf-Clauw, M., F. Chevy, and C. Ponsart. 1998. Abnormal cholesterol biosynthesis as in Smith-Lemli-Opitz syndrome disrupts normal skeletal development in the rat. J. Lab. Clin. Med. 131 : 222-227.
38. Kolf-Clauw, M., F. Chevy, B. Siliart, C. Wolf, N. Mulliez, and C. Roux. 1997. Cholesterol biosynthesis inhibited by BM15.766 induces holoprosencephaly in the rat. Teratology. 56 : 188-200.
39. Xu, G., G. Salen, S. Shefer, G. C. Ness, T. S. Chen, Z. Zhao, and G. S. Tint. 1995. Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats. J. Clin. Invest. 95 : 76-81.
40. Fliesler, S. J., M. J. Richards, C. Miller, and N. S. Peachey. 1999. Marked alteration of sterol metabolism and composition without compromising retinal development or function. Invest. Ophthalmol. Vis. Sci. 40 : 1792-1801.
41. Fliesler, S. J., N. S. Peachey, M. J. Richards, B. A. Nagel, and D. K. Vaughan. 2004. Retinal degeneration in a rodent model of Smith- Lemli-Opitz syndrome: electrophysiologic, biochemical, and morphologic features. Arch. Ophthalmol. 122 : 1190-1200.
42. Fliesler, S. J., D. K. Vaughan, E. C. Jenewein, M. J. Richards, B. A. Nagel, and N. S. Peachey. 2007. Partial rescue of retinal function and sterol steady-state in a rat model of Smith-Lemli-Opitz syndrome. Pediatr. Res. 61 : 273-278.
43. Richards, M. J., B. A. Nagel, and S. J. Fliesler. 2006. Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith-Lemli-Opitz syndrome. Exp. Eye Res. 82 : 538-541.
44. Vaughan, D. K., N. S. Peachey, M. J. Richards, B. Buchan, and S. J. Fliesler. 2006. Light-induced exacerbation of retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. Exp. Eye Res. 82 : 496-504.
45. Chavko, M., E. M. Nemoto, and J. A. Melick. 1993. Regional lipid composition in the rat brain. Mol. Chem. Neuropathol. 18 : 123-131.
46. Fliesler, S. J., and L. Bretillon. 2010. The ins and outs of cholesterol in the vertebrate retina. J. Lipid Res. 51 : 3399-3413.
47. Lund, E. G., J. M. Guileyardo, and D. W. Russell. 1999. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc. Natl. Acad. Sci. USA. 96 : 7238-7243.
48. Russell, D. W. 2000. Oxysterol biosynthetic enzymes. Biochim. Biophys. Acta. 1529 : 126-135.
49. Albro, P. W., J. T. Corbett, and J. L. Schroeder. 1994. Doubly allylic hydroperoxide formed in the reaction between sterol 5,7-dienes and singlet oxygen. Photochem. Photobiol. 60 : 310-315.
50. Albro, P. W., P. Bilski, J. T. Corbett, J. L. Schroeder, and C. F. Chignell. 1997. Photochemical reactions and phototoxicity of sterols: novel self-perpetuating mechanism for lipid photooxidation. Photochem. Photobiol. 66 : 316-325.
51. Fieser, L., and R. Stevenson. 1954. Cholesterol and companions. IX. Oxidation of Δ5-cholestene-3-one with lead tetraacetate. J. Am. Chem. Soc. 76 : 1728-1733.
52. Rosenheim, O., and W. W. Starling. 1937. The action of selenium dioxide on sterols and bile acids. Part III. Cholesterol. J. Chem. Soc. 377-384.
53. Pelc, B. 1974. 4alpha-Hydroxycholecalciferol and an attempted synthesis of its 4-beta-hydroxy-epimer. J. Chem. Soc., Perkin Trans. 1 1436-1438.
54. Gill, H. S., J. M. Londowski, R. A. Corradino, A. R. Zinsmeister, and R. Kumar. 1988. The synthesis and biological activity of 25-hydroxy-26,27- dimethylvitamin D3 and 1,25-dihydroxy-26,27-dimethylvitamin D3: highly potent novel analogs of vitamin D3. J. Steroid Biochem. 31 : 147-160.
55. Roux, C., C. Horvath, and R. Dupuis. 1979. Teratogenic action and embryo lethality of AY 9944R. Prevention by a hypercholesterolemia- provoking diet. Teratology. 19 : 35-38.
56. Gofflot, F., M. Kolf-Clauw, F. Clotman, C. Roux, and J. J. Picard. 1999. Absence of ventral cell populations in the developing brain in a rat model of the Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 87 : 207-216.
57. Roux, C., R. Dupuis, C. Horvath, and J. N. Talbot. 1980. Teratogenic effect of an inhibitor of cholesterol synthesis (AY 9944) in rats: correlation with maternal cholesterolemia. J. Nutr. 110 : 2310-2312.
58. Pulfer, M. K., and R. C. Murphy. 2004. Formation of biologically active oxysterols during ozonolysis of cholesterol present in lung surfactant. J. Biol. Chem. 279 : 26331-26338.
59. Björkhem, I., L. Starck, U. Andersson, D. Lutjohann, S. von Bahr, I. Pikuleva, A. Babiker, and U. Diczfalusy. 2001. Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S- and 27-hydroxycholesterol. J. Lipid Res. 42 : 366-371.
60. Bodin, K., L. Bretillon, Y. Aden, L. Bertilsson, U. Broome, C. Einarsson, and U. Diczfalusy. 2001. Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J. Biol. Chem. 276 : 38685-38689.
61. Bodin, K., U. Andersson, E. Rystedt, E. Ellis, M. Norlin, I. Pikuleva, G. Eggertsen, I. Bjorkhem, and U. Diczfalusy. 2002. Metabolism of 4 beta-hydroxycholesterol in humans. J. Biol. Chem. 277 : 31534-31540.
62. Breuer, O., S. Dzeletovic, E. Lund, and U. Diczfalusy. 1996. The oxysterols cholest-5-ene-3 beta,4 alpha-diol, cholest-5-ene-3 beta,4 beta-diol and cholestane-3 beta,5 alpha,6 alpha-triol are formed during in vitro oxidation of low density lipoprotein, and are present in human atherosclerotic plaques. Biochim. Biophys. Acta. 1302 : 145-152.
63. Brown, M. S., and J. L. Goldstein. 1974. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fi broblasts by 7-ketocholesterol. J. Biol. Chem. 249 : 7306-7314.
64. Hughes, H., B. Mathews, M. L. Lenz, and J. R. Guyton. 1994. Cytotoxicity of oxidized LDL to porcine aortic smooth muscle cells is associated with the oxysterols 7-ketocholesterol and 7-hydroxycholesterol. Arterioscler. Thromb. 14 : 1177-1185.
65. Vejux, A., L. Malvitte, and G. Lizard. 2008. Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis. Braz. J. Med. Biol. Res. 41 : 545-556.
66. Moreira, E. F., I. M. Larrayoz, J. W. Lee, and I. R. Rodriguez. 2009. 7-Ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation. Invest. Ophthalmol. Vis. Sci. 50 : 523-532.
67. Rodriguez, I. R., and I. M. Larrayoz. 2010. Cholesterol oxidation in the retina: implications of 7KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res. 51 : 2847-2862.
68. Smith, L. L. 1987. Cholesterol autoxidation 1981-1986. Chem. Phys. Lipids. 44 : 87-125.
69. Brown, A. J., S. L. Leong, R. T. Dean, and W. Jessup. 1997. 7-Hydroperoxycholesterol and its products in oxidized low density lipoprotein and human atherosclerotic plaque. J. Lipid Res. 38 : 1730-1745.
70. Murphy, R. C., and K. M. Johnson. 2008. Cholesterol, reactive oxygen species, and the formation of biologically active mediators. J. Biol. Chem. 283 : 15521-15525.
71. Rodriguez, I. R., and S. J. Fliesler. 2009. Photodamage generates 7-keto- and 7-hydroxycholesterol in the rat retina via a free radicalmediated mechanism. Photochem. Photobiol. 85 : 1116-1125
72. Song, W., W. M. Pierce, Y. Saeki, R. N. Redinger, and R. A. Prough. 1996. Endogenous 7-oxocholesterol is an enzymatic product: characterization of 7 alpha-hydroxycholesterol dehydrogenase activity of hamster liver microsomes. Arch. Biochem. Biophys. 328 : 272-282.
73. Shinkyo, R., L. Xu, K. A. Tallman, Q. Cheng, N. A. Porter, and F. P. Guengerich. 2011. Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate. J. Biol. Chem. Epub ahead of print. August 3, 2011; doi: 10.1074/jbc. M111.282434. PubMed
74. De Fabiani, E., D. Caruso, M. Cavaleri, M. Galli Kienle, and G. Galli. 1996. Cholesta-5,7,9(11)-trien-3 beta-ol found in plasma of patients with Smith-Lemli-Opitz syndrome indicates formation of sterol hydroperoxide. J. Lipid Res. 37 : 2280-2287.
75. Kelley, R. I. 2000. Inborn errors of cholesterol biosynthesis. Adv. Pediatr. 47 : 1-53.