Recent advances in understanding the STSL locus and ABCG5/ABCG8 biology

Current Opinion in Lipidology

Volumn 25, Issue 3, 2014, Pages 169-175

  Patel, Shailendra B ^a,b  

^a CLEMENT J ZABLOCKI VETERANS AFFAIRS MEDICAL CENTER   (United States)

^b MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

ABCG5; phytosterols; pleiotropy; toxicity; xenosterols

Indexed keywords

ABC TRANSPORTER G5; ABC TRANSPORTER G8; CAMPESTEROL; CHOLESTANETRIOL 26 MONOOXYGENASE; CHOLESTEROL; CHOLESTEROL 7ALPHA MONOOXYGENASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; LIVER X RECEPTOR; PHYTOSTEROL; SITOSTEROL; STEROL; STIGMASTEROL; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN; ABC TRANSPORTER; ABCG5 PROTEIN, HUMAN; ABCG5 PROTEIN, MOUSE; ABCG8 PROTEIN, HUMAN; ABCG8 PROTEIN, MOUSE; LIPOPROTEIN; ORPHAN NUCLEAR RECEPTOR;

ABDOMINAL FAT; ALLELE; ANEMIA; ARTERY WALL; BILE DUCT CANCER; CARCINOGENESIS; CARDIOMYOPATHY; CAROTID ARTERY DISEASE; CAUCASIAN; CHOLELITHIASIS; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; CHOLESTEROL STONE; CORONARY ARTERY DISEASE; DISORDERS OF LIPID METABOLISM; ETHNIC GROUP; FERTILITY; GALLSTONE FORMATION; GENE LOCUS; GENE MAPPING; GENE MUTATION; GENETIC SUSCEPTIBILITY; HEMOLYSIS; HUMAN; INFERTILITY; INTRACELLULAR SIGNALING; INTRON; LIPID LIVER LEVEL; LIPID STORAGE; LIPID TRANSPORT; LIVER DISEASE; LIVER DYSFUNCTION; LIVER INJURY; LONGEVITY; METABOLIC REGULATION; NONHUMAN; PARENTERAL NUTRITION; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROMOTER REGION; PROTECTION; REVIEW; SITOSTEROLEMIA; SPONTANEOUS MUTATION; STSL GENE; THROMBOCYTE ACTIVATION; THROMBOCYTE MEMBRANE; THROMBOCYTOPENIA; THROMBOCYTOPOIESIS; TRANSCRIPTION REGULATION; XENOSTEROL; ACTIVE TRANSPORT; ANIMAL; CELL MEMBRANE; DISORDERS OF LIPID AND LIPOPROTEIN METABOLISM; ENTEROPATHY; GENETIC POLYMORPHISM; GENETICS; HYPERCHOLESTEROLEMIA; METABOLISM; MOUSE; MUTATION; THROMBOCYTE;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BIOLOGICAL TRANSPORT, ACTIVE; BLOOD PLATELETS; CELL MEMBRANE; GENETIC LOCI; HUMANS; HYPERCHOLESTEROLEMIA; INTESTINAL DISEASES; LIPID METABOLISM, INBORN ERRORS; LIPOPROTEINS; MICE; MUTATION; ORPHAN NUCLEAR RECEPTORS; PHYTOSTEROLS; POLYMORPHISM, GENETIC; PROMOTER REGIONS, GENETIC; STEROLS;

EID: 84900509961     PISSN: 09579672     EISSN: 14736535     Source Type: Journal    
DOI: 10.1097/MOL.0000000000000071     Document Type: Review

References (71)

1. Bhattacharyya AK, Connor WE. Beta-sitosterolemia xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 1974; 53:1033-1043.
2. Patel SB, Sale n G, Hidaka H, et al. Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J Clin Invest 1998; 102:1041-1044.
3. Berge KE, T ian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290:1771-1775.
4. Lee M-H, Lu K, Hazard S, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Gen 2001; 27:79-83.
5. Lu K, Lee M-H, Carpten JD, et al. High-resolution physical and transcript map of human chromosome 2p21 containing the Sitosterolemia locus. Eur Hum Genet 2001; 9:364-374.
6. Lu K, Lee M-H, Hazard S, et al. Two genes that map to the STSL locus cause Sitostero lemia: Genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8 respectively. Am J Hum Genet 2001; 69:278-290.
7. Graf GA, Li WP, Gerard RD, et al. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest 2002; 110:659-669.
8. Graf GA, Yu L, Li WP, et al. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem 2003; 278:48275-48282.
9. Yu L, Gupta S, Xu F, et al. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem 2005; 280:8742-8747.
10. Wang J, Sun F, Zhang DW, et al. Sterol transfer by ABCG5 and ABCG8: In vitro assay and reconstitution. J Biol Chem 2006; 281:27894-27904.
11. Zhang DW, Graf GA, Gerard RD, et al. Functional asymmetry of nucleotidebinding domains in ABCG5 and ABCG8. J Biol Chem 2006; 281:4507-4516.
12. Yu L, von Bergmann K, Lutjohann D, et al. Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J Lipid Res 2004; 45:301-307.
13. Patel SB, Salen G. Sitosterolemia: Xenophobia for the body. In: Vissers MN, Kastelein JJP, Stroes ES, editors. Evidence-based management of lipid disorders. Harley, UK: TFM Publishing Ltd; 2010. pp. 217-230.
14. Yu L, Hammer RE, Li-Hawkins J, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A 2002; 99:16237-16242.
15. Klett EL,Lu K,Kosters A,et al. A mouse model of sitosterolemia: Absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol. BMC Med, 2004, 2, 5.
16. Plosch T, Bloks VW, Terasawa Y, et al. Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor. Gastroent erology 2004; 126:290-300.
17. Chase TH, Lyons BL, Bronson RT, et al. The mouse mutation ?thrombocytopenia and cardiomyopathy? (trac) disrupts Abcg5: A spontaneous single gene model for human heredita ry phytosterolemia/sitosterolemia. Blood 2010; 115:1267-1276.
18. Buch S, Schafmayer C, Volzke H, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 2007; 39:995-999.
19. Wang Y, Jiang ZY, Fei J, et al. ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males. Clin Chim Acta 2007; 384:80-85.
20. Caamano JM, Pacheco A, Lanas F, Salazar LA. Single nucleotide polymorphisms in ABCG5 and ABCG8 genes in Chilean subjects with polygeni c hypercholesterolemia and controls. Clin Chem Lab Med 2008; 46:1581-1585.
21. Junyent M, Tucker KL, Smith CE, et al. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentration s depend on smoking habit in the Boston Puerto Rican Health Study. J Lipid Res 2009; 50:2009; 46:565-573.
22. Kuo KK, Shin SJ, Chen ZC, et al. Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease. Br J Surg 2008; 95:1005-1011.
23. Srivastava A, Tulsyan S, Pandey SN, et al. Single nucleotide polymorphism in the ABCG8 transporter gene is associated with gallbladder cancer susceptibility. Liver Int 2008; 29:831-837.
24. Zhao HL, Houweling AH, Vanstone CA, et al. Genetic variation in ABC G5/G8 and NPC1L1 impact cholesterol response to plant sterols in hypercholesterolemic men. Lipids 2008; 43:1155-1164.
25. Aulchenko YS, Ripatti S, Lindqvist I, et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009; 41:47-55.
26. Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009; 41:56-65.
27. Garcia-Rios A, Perez-Martinez P, Fuentes F, et al. Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hyperchole sterolemia. Atherosclerosis 2010; 210:486-492.
28. Jakulj L, Vissers MN, Tanck MW, et al. ABCG5/G8 polymorphisms and markers of cholesterol metabolism: Systematic review and meta-analysis. J Lipid Res 2010; 51:3016-3023.
29. Ma L, Yang J, Runesha HB, et al. Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham Heart S tudy data. BMC Med Genet 2010; 11:55.
30. Repa JJ, Berge KE, Pomajzl C, et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 2002; 277:18793-18800.
31. Freeman LA, Kennedy A, Wu J, et al. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. J Lipid Res 2004; 45:1197-1206.
32. Sumi K, Tanaka T, Uchida A, et al. Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8. Mol Cell Biol 2007; 27:4248-4260.
33. Salen G, von Bergmann K, Lutjohann D, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 2004; 109:966-971.
34. Yu L, von Bergmann K, Lutjohann D, et al. Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8. J Lipid Res 2005; 46:1739-1744.
35. Pollack OJ. Reduction of blood cholesterol in man. Circulation 1953; 7:703-706.
36. Best MM,Duncan CH,VanLoon EJ,Wathen JD. Lowering of serum cholesterol by the administration of a plant sterol. Circulation, 1954, 10, 201-206.
37. Matsuoka K, Kajimoto E, Horiuchi M, et al. Competitive solubilization of cholesterol and six species of sterol/stanol in bile salt micelles. Chem Phys Lipids 2010; 163:397-402.
38. Clayton PT, Bowron A, Mills KA, et al. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 1993; 105:1806-1813.
39. Wittenburg H, Lyons MA, Li R, et al. Association of a lithogenic Abcg5/Abcg8 allele on Ch romosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome 2005; 16:495-504.
40. Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Sterol transporter ad enosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62 000 individuals from the general population. Hepatology 2011; 53:640-648.
41. Renner O, Lutjohann D, Richter D, et al. Role of the ABCG8 19H risk allele in cholesterol absorption and gallstone disease. BMC Gastroenterol 2013; 13:30.
42. von Kampen O, Buch S, Nothnagel M, et al. Genetic and functi onal identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus. Hepatology 2013; 57:2407-2417.
43. Teupser D, Baber R, Ceglarek U, et al. G enetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet 2010; 3:331-339. Linking phystosterols to atherosclerosis is not new, but these authors used a genome-wide association study tha t linked these not only to the STSL locus, but also to the ABO locus.
44. Horenstein RB, Mitchell BD, Post WS, et al. The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Orde r Amish. Arterioscler Thromb Vasc Biol 2013; 33:413-419.
45. Solca C, Stanga Z, Pandit B, et al. Sitosterolaemia in Switzerland: Molecular genetics links the US Amish-Mennonites to their European roots. Clin Genet 2005; 68:174-178.
46. Back SS, Kim J, Choi D, et al. Cooperative transcriptional activation of ATPbinding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear recepto rs including liver-X-receptor. BMB Rep 2013; 46:322-327.
47. Cook PR, Lang J. The spatial organization of sequences involved in initiation and termination of eukaryotic DNA replication. Nucleic Acids Res 1984; 12:1069-1075.
48. Jackson DA,McCready SJ, Cook PR. Replication and transcription depend on attachment of DNA to the nuclear cage. J Cell Sci Suppl 1984; 1:59-79.
49. Cook PR, Brazell IA. Mapping sequences in loops of nuclear DNA by their progressive detachment from the nuclear cage. Nucleic Acids Res 1980; 8:2895-2906.
50. Cook PR. Hypothesis on d ifferentiation and the inheritance of gene superstructure. Nature 1973; 245:23-25.
51. Su K, Sabeva NS, Liu J, et al. The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver dis ease and loss of glycemic control independently of phytosterol accumulation. J Biol Chem 2012; 287:28564-28575.
52. Su K, Sabeva NS, Wang Y, et al. Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arterioscler Thromb Vasc Biol 2014; 34:26-33.
53. Mendez-Gonzá lez J, Julve J, Rotllan N, et al. ATP-binding cassette G5/G8 deficiency causes hypertriglyceridemia by affecting multiple metabolic pathways. Biochim Biophys Acta 2011; 1811:1186-1193.
54. Wilund KR, Yu L, Xu F, et al. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol 2004; 24:2326-2332.
55. S olca C, Tint GS, Patel SB. Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice. J Lipid Res 2013; 54:397-409.
56. McDaniel AL, Alger HM, S awyer JK, et al. Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice. Am J Pathol 2013; 182:1131-1138.
57. Wilson DW, Oslund KL, Lyons B, et al. Inflammatory dilated cardiomyopathy in Abcg5-deficient mice. Toxicol Pathol 2013; 41:880-892.
58. Shefer S,Salen G,Bullock J,et al, The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutary l-coenzyme A reductase and cholesterol 7 alpha-hydroxylase in the rat and sitosterolemic homozygotes. Hepatology, 1994, 20(1 Pt 1) 213-219.
59. Nguyen LB, Shefer S, Salen G, et al. Competitive in hibition of hepatic sterol 27-hydroxylase by sitosterol: Decreased activity in sitosterolemia. Proc Assoc Am Physicians 1998; 110:32-39.
60. Fernandez C, Suarez Y, Ferruelo AJ, et al. Inhibition of cholesterol biosynthesis by Delta22-unsaturated phytosterols via competitive inhibition of sterol Delta 24-reductase in mammalian cells. Biochem J 2002; 366 (Pt 1):109-119.
61. Kurano M, Iso ON, Hara M , et al. Plant sterols increased IL-6 and TNF-alpha secretion from macrophages, but to a lesser extent than cholesterol. J Atheroscler Thromb 2011; 18:373-383.
62. El Kasmi KC, Anderson AL, Deve reaux MW, et al. Phytosterols promote liver injury and kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 2013; 5:206ra137.
63. El Kasmi KC, Anderson AL, Deverea ux MW, et al. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 2012; 55:1518-1528.
64. Rees DC, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 2005; 130:297-30 9.
65. Kruit JK, Drayer AL, Bloks VW, et al. Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia. J Biol Chem 2008; 283:6281-6287.
66. Kanaji T, Kanaji S, Montgomery RR, et al. Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of Sitosterolemia. Blood 2013; 122:2732-2742.
67. Dietschy JM, Turley SD. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004; 45:1375-1397.
68. Vanmierlo T, P opp J, Kolsch H, et al. The plant sterol brassicasterol as additional CSF biomarker in Alzheimer?s disease. Acta Psychiatr Scand 2011; 124:184-192.
69. Tansley G, Holmes DT, Lutjohann D, et al. Sterol lipid metabolism in Down syndrome revisited: Down syndrome is associated with a selective reduction in serum brassicasterol levels. Curr Gerontol Geriatr Res 2012; 2012:179318.
70. Vanmierlo T, Rutten K, van Vark-van der Zee LC, et al. Cerebral accumulation of dietary derivable plant sterols does not interfere with memory and anxiety related behavior in Abcg5-/- mice. Plant Foods Hum Nutr 2011; 66:149-15 6.
71. Vanmierlo T, Weingartner O, van der Pol S, et al. Dietary intake of plant sterols stably increases plant sterol levels in the murine brain. J Lipid Res 2012; 53:726-735.