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. 1998 Sep 1;102(5):1041–1044. doi: 10.1172/JCI3963

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

S B Patel 1, G Salen 1, H Hidaka 1, P O Kwiterovich 1, A F Stalenhoef 1, T A Miettinen 1, S M Grundy 1, M H Lee 1, J S Rubenstein 1, M H Polymeropoulos 1, M J Brownstein 1
PMCID: PMC508970  PMID: 9727073

Abstract

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

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Selected References

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  1. Beaty T. H., Kwiterovich P. O., Jr, Khoury M. J., White S., Bachorik P. S., Smith H. H., Teng B., Sniderman A. Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia. Am J Hum Genet. 1986 Apr;38(4):492–504. [PMC free article] [PubMed] [Google Scholar]
  2. Berger G. M., Deppe W. M., Marais A. D., Biggs M. Phytosterolaemia in three unrelated South African families. Postgrad Med J. 1994 Sep;70(827):631–637. doi: 10.1136/pgmj.70.827.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berger G. M., Pegoraro R. J., Patel S. B., Naidu P., Rom L., Hidaka H., Marais A. D., Jadhav A., Naoumova R. P., Thompson G. R. HMG-CoA reductase is not the site of the primary defect in phytosterolemia. J Lipid Res. 1998 May;39(5):1046–1054. [PubMed] [Google Scholar]
  4. Bhattacharyya A. K., Connor W. E. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974 Apr;53(4):1033–1043. doi: 10.1172/JCI107640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bhattacharyya A. K., Connor W. E., Lin D. S., McMurry M. M., Shulman R. S. 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. 1991 Sep-Oct;11(5):1287–1294. doi: 10.1161/01.atv.11.5.1287. [DOI] [PubMed] [Google Scholar]
  6. Gregg R. E., Connor W. E., Lin D. S., Brewer H. B., Jr Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis. J Clin Invest. 1986 Jun;77(6):1864–1872. doi: 10.1172/JCI112513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hidaka H., Nakamura T., Aoki T., Kojima H., Nakajima Y., Kosugi K., Hatanaka I., Harada M., Kobayashi M., Tamura A. Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis. J Lipid Res. 1990 May;31(5):881–888. [PubMed] [Google Scholar]
  8. Hidaka H., Sugiura H., Nakamura T., Kojima H., Fujita M., Sugie N., Okabe H., Nishio Y., Maegawa H., Kashiwagi A. beta-Sitosterolemia with generalized eruptive xanthomatosis. Endocr J. 1997 Feb;44(1):59–64. doi: 10.1507/endocrj.44.59. [DOI] [PubMed] [Google Scholar]
  9. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  10. Kwiterovich P. O., Jr, Bachorik P. S., Smith H. H., McKusick V. A., Connor W. E., Teng B., Sniderman A. D. Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. Lancet. 1981 Feb 28;1(8218):466–469. doi: 10.1016/s0140-6736(81)91850-x. [DOI] [PubMed] [Google Scholar]
  11. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Miettinen T. A. 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. 1980 Feb;10(1):27–35. doi: 10.1111/j.1365-2362.1980.tb00006.x. [DOI] [PubMed] [Google Scholar]
  13. Nguyen L. B., Salen G., Shefer S., Bullock J., Chen T., Tint G. S., Chowdhary I. R., Lerner S. Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis. Metabolism. 1994 Jul;43(7):855–859. doi: 10.1016/0026-0495(94)90266-6. [DOI] [PubMed] [Google Scholar]
  14. Nguyen L. B., Salen G., Shefer S., Tint G. S., Shore V., Ness G. C. 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. 1990 Apr;39(4):436–443. doi: 10.1016/0026-0495(90)90260-j. [DOI] [PubMed] [Google Scholar]
  15. Nguyen L. B., Shefer S., Salen G., Ness G. C., Tint G. S., Zaki F. G., Rani I. A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J Clin Invest. 1990 Sep;86(3):923–931. doi: 10.1172/JCI114794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Patel S. B., Honda A., Salen G. Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J Lipid Res. 1998 May;39(5):1055–1061. [PubMed] [Google Scholar]
  17. Salen G., Ahrens E. H., Jr, Grundy S. M. Metabolism of beta-sitosterol in man. J Clin Invest. 1970 May;49(5):952–967. doi: 10.1172/JCI106315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Salen G., Kwiterovich P. O., Jr, Shefer S., Tint G. S., Horak I., Shore V., Dayal B., Horak E. Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis. J Lipid Res. 1985 Feb;26(2):203–209. [PubMed] [Google Scholar]
  19. Salen G., Shefer S., Nguyen L., Ness G. C., Tint G. S., Shore V. Sitosterolemia. J Lipid Res. 1992 Jul;33(7):945–955. [PubMed] [Google Scholar]
  20. Salen G., Shore V., Tint G. S., Forte T., Shefer S., Horak I., Horak E., Dayal B., Nguyen L., Batta A. K. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J Lipid Res. 1989 Sep;30(9):1319–1330. [PubMed] [Google Scholar]
  21. Salen G., Tint G. S., Shefer S., Shore V., Nguyen L. Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia. Arterioscler Thromb. 1992 May;12(5):563–568. doi: 10.1161/01.atv.12.5.563. [DOI] [PubMed] [Google Scholar]
  22. Shefer S., Salen G., Bullock J., Nguyen L. B., Ness G. C., Vhao Z., Belamarich P. F., Chowdhary I., Lerner S., Batta A. K. 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. 1994 Jul;20(1 Pt 1):213–219. doi: 10.1016/0270-9139(94)90155-4. [DOI] [PubMed] [Google Scholar]
  23. Smith L. L., Johnson B. H. Biological activities of oxysterols. Free Radic Biol Med. 1989;7(3):285–332. doi: 10.1016/0891-5849(89)90136-6. [DOI] [PubMed] [Google Scholar]

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