Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice

Journal of Lipid Research

Volumn 54, Issue 2, 2013, Pages 397-409

  Solca, Curzio ^a,b,e   Tint, G Stephen ^c,d   Patel, Shailendra B ^a,b  

^a Clement J Zablocki Veterans Medical Center   (United States)

^b MEDICAL COLLEGE OF WISCONSIN   (United States)

^c DEPARTMENT OF VETERANS AFFAIRS   (United States)

^d RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

^e Centro Dialisi Drssa Claudia Ferrier   (Switzerland)

Author keywords

Abcg5; Abcg8; Adipocytes; Ezetimibe; Infertility; Phytosterols

Indexed keywords

EZETIMIBE; STEROL; UNCLASSIFIED DRUG; XENOSTEROL DERIVATIVE;

ABDOMINAL FAT; ADIPOCYTE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOACCUMULATION; BODY FAT; CELL COUNT; CELL SIZE; CONTROLLED STUDY; FATTY ACID METABOLISM; FEMALE; FERTILITY; GENE; GENE ACTIVITY; GENE EXPRESSION; GLUCOSE TOLERANCE TEST; INFERTILITY; KNOCKOUT MOUSE; LIPID STORAGE; LIPOLYSIS; MALE; MICROARRAY ANALYSIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; STEROLIN 1 GENE; STEROLIN 2 GENE; TOXICITY TESTING;

ABDOMINAL FAT; ADIPOCYTES; ADIPOSE TISSUE, WHITE; ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; AZETIDINES; CELL SIZE; DIETARY FATS; FATTY ACIDS; FEMALE; GENE EXPRESSION REGULATION; GENE KNOCKOUT TECHNIQUES; GLUCOSE TOLERANCE TEST; HUMANS; INFERTILITY, FEMALE; INFERTILITY, MALE; INTESTINES; LIPOPROTEINS; MALE; MICE; PHYTOSTEROLS; TESTIS;

EID: 84872435630     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M031476     Document Type: Article

References (59)

1. Chiang, J. Y. 2002. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr. Rev. 23: 443-463. (Pubitemid 34925641)
2. Kidambi, S., and S. B. Patel. 2008. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica. 38: 1119-1139.
3. Lu, K., M. H. Lee, and S. B. Patel. 2001. Dietary cholesterol absorption; more than just bile. Trends Endocrinol. Metab. 12: 314-320. (Pubitemid 33714223)
4. Lee, M-H., D. Gordon, J. Ott, K. Lu, L. Ose, T. Miettinen, H. Gylling, A. F. Stalenhoef, A. Pandya, H. Hidaka, et al. 2001. Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolemia in multiple communities. Eur. J. Hum. Genet. 9: 375-384. (Pubitemid 32499454)
5. Lee, M-H., K. Lu, S. Hazard, H. Yu, S. Shulenin, H. Hidaka, H. Kojima, R. Allikmets, N. Sakuma, R. Pegoraro, et al. 2001. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat. Genet. 27: 79-83. (Pubitemid 32044523)
6. Lu, K., M-H. Lee, S. Hazard, A. Brooks-Wilson, H. Hidaka, H. Kojima, L. Ose, A. F. H. Stanlenhoef, T. Miettinen, I. Bjorkhem, et al. 2001. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8 respectively. Am. J. Hum. Genet. 69: 278-290. (Pubitemid 32695201)
7. Patel, S. B., A. Honda, and G. Salen. 1998. Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J. Lipid Res. 39: 1055-1061. (Pubitemid 28222011)
8. Patel, S. B., G. Salen, H. Hidaka, P. O. Kwiterovich, A. F. Stalenhoef, T. A. Miettinen, S. M. Grundy, M. H. Lee, J. S. Rubenstein, M. H. Polymeropoulos, et al. 1998. Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J. Clin. Invest. 102: 1041-1044. (Pubitemid 28419249)
9. Lutjohann, D., I. Bjorkhem, U. F. Beil, and K. von Bergmann. 1995. Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J. Lipid Res. 36: 1763-1773.
10. Miettinen, T. A. 1980. Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur. J. Clin. Invest. 10: 27-35. (Pubitemid 10133847)
11. Salen, G., S. B. Patel, and A. K. Batta. 2002. Sitosterolemia. Cardiovasc. Drug Rev. 20: 255-270. (Pubitemid 36105780)
12. Salen, G., V. Shore, G. S. Tint, T. Forte, S. Shefer, I. Horak, E. Horak, B. Dayal, L. Nguyen, A. K. Batta, et al. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J. Lipid Res. 1989. 30: 1319-1330. (Pubitemid 19253283)
13. Salen, G., G. S. Tint, S. Shefer, V. Shore, and L. Nguyen. 1992. Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia. Arterioscler. Thromb. 12: 563-568.
14. Shulman, R. S., A. K. Bhattacharyya, W. E. Connor, and D. S. Fredrickson. 1976. Beta-sitosterolemia and xanthomatosis. N. Engl. J. Med. 294: 482-483.
15. Berge, K. E., H. Tian, G. A. Graf, L. Yu, N. V. Grishin, J. Schultz, P. Kwiterovich, B. Shan, R. Barnes, and H. H. Hobbs. 2000. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 290: 1771-1775. (Pubitemid 32004809)
16. Bhattacharyya, A. K., W. E. Connor, D. S. Lin, M. M. McMurry, and R. S. Shulman. 1991. Sluggish sitosterol turnover and hepatic failure to excrete sitosterol into bile cause expansion of body pool of sitosterol in patients with sitosterolemia and xanthomatosis. Arterioscler. Thromb. 11: 1287-1294.
17. Graf, G. A., W. P. Li, R. D. Gerard, I. Gelissen, A. White, J. C. Cohen, and H. H. Hobbs. 2002. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J. Clin. Invest. 110: 659-669. (Pubitemid 34988790)
18. Repa, J. J., K. E. Berge, C. Pomajzl, J. A. Richardson, H. Hobbs, and D. J. Mangelsdorf. 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277: 18793-18800. (Pubitemid 34952438)
19. Graf, G. A., L. Yu, W. P. Li, R. Gerard, P. L. Tuma, J. C. Cohen, and H. H. Hobbs. 2003. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J. Biol. Chem. 278: 48275-48282. (Pubitemid 37523283)
20. Klett, E. L., K. Lu, A. Kosters, E. Vink, M. H. Lee, M. Altenburg, S. Shefer, A. K. Batta, H. Yu, J. Chen, et al. 2004. A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol. BMC Med. 2: 5.
21. Plosch, T., V. W. Bloks, Y. Terasawa, S. Berdy, K. Siegler, F. Van Der Sluijs, I. P. Kema, A. K. Groen, B. Shan, F. Kuipers, et al. 2004. Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor. Gastroenterology. 126: 290-300. (Pubitemid 38040743)
22. Yu, L., R. E. Hammer, J. Li-Hawkins, K. Von Bergmann, D. Lutjohann, J. C. Cohen, and H. H. Hobbs. 2002. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA. 99: 16237-16242. (Pubitemid 35462779)
23. Yu, L., J. Li-Hawkins, R. E. Hammer, K. E. Berge, J. D. Horton, J. C. Cohen, and H. H. Hobbs. 2002. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J. Clin. Invest. 110: 671-680. (Pubitemid 34988791)
24. Yu, L., K. von Bergmann, D. Lutjohann, H. H. Hobbs, and J. C. Cohen. 2004. Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J. Lipid Res. 45: 301-307. (Pubitemid 38228828)
25. Gregg, R. E., W. E. Connor, D. S. Lin, and H. Brewer, Jr. 1986. Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis. J. Clin. Invest. 77: 1864-1872. (Pubitemid 16062641)
26. Chen, J., A. Batta, S. Zheng, W. R. Fitzgibbon, M. E. Ullian, H. Yu, P. Tso, G. Salen, and S. B. Patel. 2005. The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension. BMC Genet. 6: 40.
27. Grefhorst, A., B. M. Elzinga, P. J. Voshol, T. Plosch, T. Kok, V. W. Bloks, F. H. van der Sluijs, L. M. Havekes, J. A. Romijn, H. J. Verkade, et al. 2002. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J. Biol. Chem. 277: 34182-34190.
28. Yang, J., J. L. Goldstein, R. E. Hammer, Y. A. Moon, M. S. Brown, and J. D. Horton. 2001. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc. Natl. Acad. Sci. USA. 98: 13607-13612. (Pubitemid 33115945)
29. Livak, K. J., and T. D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25: 402-408. (Pubitemid 34164012)
30. Haemmerle, G., A. Lass, R. Zimmermann, G. Gorkiewicz, C. Meyer, J. Rozman, G. Heldmaier, R. Maier, C. Theussl, S. Eder, et al. 2006. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 312: 734-737.
31. Soni, K. G., R. Lehner, P. Metalnikov, P. O'Donnell, M. Semache, W. Gao, K. Ashman, A. V. Pshezhetsky, and G. A. Mitchell. 2004. Carboxylesterase 3 (EC 3.1.1.1) is a major adipocyte lipase. J. Biol. Chem. 279: 40683-40689. (Pubitemid 39287663)
32. Honda, A., G. Salen, L. B. Nguyen, G. S. Tint, A. K. Batta, and S. Shefer. 1998. Down-regulation of cholesterol biosynthesis in sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglutaryl- CoA synthase, reducatse, squalene synthase and 7-dehydrocholesterol delta-7 reductase in liver and mononuclear leucocytes. J. Lipid Res. 39: 44-50. (Pubitemid 28063541)
33. Yang, C., L. Yu, W. Li, F. Xu, J. C. Cohen, and H. H. Hobbs. 2004. Disruption of cholesterol homeostasis by plant sterols. J. Clin. Invest. 114: 813-822. (Pubitemid 39578740)
34. Patel, S. B., and G. Salen. 2010. Sitosterolemia: xenophobia for the body. In Evidence-based Management of Lipid Disorders. M. N. Vissers, J. J. P. Kastelein, and E. S. Stroes, editors. TFM Publishing, Harley, UK. 217-230.
35. Mushtaq, T., J. K. Wales, and N. P. Wright. 2007. Adrenal insufficiency in phytosterolaemia. Eur. J. Endocrinol. 157 (Suppl. 1): S61-S65. (Pubitemid 47434132)
36. Nguyen, L. B., G. Salen, S. Shefer, J. Bullock, T. Chen, G. S. Tint, I. R. Chowdhary, and S. Lerner. 1994. Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis. Metabolism. 43: 855-859. (Pubitemid 24213304)
37. Nguyen, L. B., G. Salen, S. Shefer, G. S. Tint, V. Shore, and G. C. Ness. 1990. Decreased cholesterol biosynthesis in sitosterolemia with xanthomatosis: diminished mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and enzyme protein associated with increased low-density lipoprotein receptor function. Metabolism. 39: 436-443. (Pubitemid 20146597)
38. Nguyen, L. B., S. Shefer, G. Salen, G. C. Ness, G. S. Tint, F. G. Zaki, and I. Rani. 1990. A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J. Clin. Invest. 86: 923-931. (Pubitemid 20327385)
39. Shefer, S., G. Salen, J. Bullock, L. B. Nguyen, G. C. Ness, Z. Vhao, P. F. Belamarich, I. Chowdhary, S. Lerner, A. K. Batta, et al. 1994. The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl- coenzyme A reductase and cholesterol 7 alpha-hydroxylase in the rat and sitosterolemic homozygotes. Hepatology. 20: 213-219.
40. Carter, B. A., O. A. Taylor, D. R. Prendergast, T. L. Zimmerman, R. Von Furstenberg, D. D. Moore, and S. J. Karpen. 2007. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr. Res. 62: 301-306. (Pubitemid 47301479)
41. Gilman, C. I., F. D. Leusch, W. C. Breckenridge, and D. L. MacLatchy. 2003. Effects of a phytosterol mixture on male fish plasma lipoprotein fractions and testis P450scc activity. Gen. Comp. Endocrinol. 130: 172-184. (Pubitemid 36268771)
42. Leusch, F. D., and D. L. MacLatchy. 2003. In vivo implants of beta-sitosterol cause reductions of reactive cholesterol pools in mitochondria isolated from gonads of male goldfish (Carassius auratus). Gen. Comp. Endocrinol. 134: 255-263. (Pubitemid 37443481)
43. MacLatchy, D. L., and G. J. Van Der Kraak. 1995. The phytoestrogen beta-sitosterol alters the reproductive endocrine status of goldfish. Toxicol. Appl. Pharmacol. 134: 305-312.
44. Mattsson, K., J. Tana, C. Engstrom, J. Hemming, and K. J. Lehtinen. 2001. Effects of wood-related sterols on the offspring of the viviparous blenny, Zoarces viviparus L. Ecotoxicol. Environ. Saf. 49: 122-130. (Pubitemid 32531160)
45. Nakari, T., and K. Erkomaa. 2003. Effects of phytosterols on zebrafish reproduction in multigeneration test. Environ. Pollut. 123: 267-273. (Pubitemid 36292196)
46. Sharpe, R. L., A. Woodhouse, T. W. Moon, V. L. Trudeau, and D. L. Maclatchy. 2007. Beta-sitosterol and 17beta-estradiol alter gonadal steroidogenic acute regulatory protein (StAR) expression in goldfish, Carassius auratus. Gen. Comp. Endocrinol. 15: 34-41. (Pubitemid 46241116)
47. Awad, A. B., A. C. Downie, and C. S. Fink. 2000. Inhibition of growth and stimulation of apoptosis by beta-sitosterol treatment of MDA-MB-231 human breast cancer cells in culture. Int. J. Mol. Med. 5: 541-545.
48. Berges, R. R., J. Windeler, H. J. Trampisch, and T. Senge. 1995. Randomised, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Lancet. 345: 1529-1532.
49. Cabeza, M., E. Bratoeff, I. Heuze, E. Ramirez, M. Sanchez, and E. Flores. 2003. Effect of beta-sitosterol as inhibitor of 5 alpha-reductase in hamster prostate. Proc. West. Pharmacol. Soc. 46: 153-155. (Pubitemid 37463459)
50. Nguyen, L. B., S. Shefer, G. Salen, S. G. Tint, and A. K. Batta. 1998. Competitive inhibition of hepatic sterol 27-hydroxylase by sitosterol: decreased activity in sitosterolemia. Proc. Assoc. Am. Physicians. 110: 32-39. (Pubitemid 28051636)
51. Prager, N., K. Bickett, N. French, and G. Marcovici. 2002. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J. Altern. Complement. Med. 8: 143-152. (Pubitemid 34438487)
52. Vivancos, M., and J. J. Moreno. 2005. Beta-sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic. Biol. Med. 39: 91-97. (Pubitemid 40733119)
53. Fernandez, C., Y. Suarez, A. J. Ferruelo, D. Gomez-Coronado, and M. A. Lasuncion. 2002. Inhibition of cholesterol biosynthesis by Delta22-unsaturated phytosterols via competitive inhibition of sterol Delta24-reductase in mammalian cells. Biochem. J. 366: 109-119. (Pubitemid 34971809)
54. Katamoto, H., S. Kurihara, and Y. Shimada. 1990. Effects of isoprothiolane and phytosterol on lipogenesis and lipolysis in adipocytes from rats of dietary fat necrosis. Nippon Juigaku Zasshi. 52: 1189-1197.
55. Katamoto, H., N. Yoneda, and Y. Shimada. 1991. Effects of isoprothiolane and phytosterol on adipocyte metabolism and fatty acid composition of serum and tissue lipids in rats. J. Vet. Med. Sci. 53: 905-910.
56. Vanmierlo, T., O. Weingartner, S. van der Pol, C. Husche, A. Kerksiek, S. Friedrichs, E. Sijbrands, H. Steinbusch, M. Grimm, T. Hartmann, et al. 2012. Dietary intake of plant sterols stably increases plant sterol levels in the murine brain. J. Lipid Res. 53: 726-735.
57. Vanmierlo, T., K. Rutten, L. C. van Vark-van der Zee, S. Friedrichs, V. W. Bloks, A. Blokland, F. C. Ramaekers, E. Sijbrands, H. Steinbusch, J. Prickaerts, et al. 2011. Cerebral accumulation of dietary derivable plant sterols does not interfere with memory and anxiety related behavior in Abcg5-/- mice. Plant Foods Hum. Nutr. 66: 149-156.
58. Byskov, A. G., C. Y. Andersen, L. Leonardsen, and M. Baltsen. 1999. Meiosis activating sterols (MAS) and fertility in mammals and man. J. Exp. Zool. 285: 237-242. (Pubitemid 29475433)
59. Rozman, D. 2000. Lanosterol 14alpha-demethylase (CYP51)-a cholesterol biosynthetic enzyme involved in production of meiosis activating sterols in oocytes and testis-a minireview. Pflugers Arch. 439 (3 Suppl.): R56-R57.