The ABCG5 ABCG8 sterol transporter and phytosterols: Implications for cardiometabolic disease

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 16, Issue 2, 2009, Pages 172-177

  Sabeva, Nadezhda S ^a   Liu, Jingjing ^a   Graf, Gregory A ^a  

^a University of Kentucky   (United States)

Author keywords

ABCG5; ABCG8; Atherosclerosis; Cholesterol; Phytosterol

Indexed keywords

ABC TRANSPORTER; ATP BINDING CASSETTE TRANSPORTER G5; ATP BINDING CASSETTE TRANSPORTER G8; EZETIMIBE; LEPTIN; PHYTOSTEROL; SITOSTEROL; STANOL ESTER; STEROL; UNCLASSIFIED DRUG; XENOBIOTIC AGENT; ABCG5 PROTEIN, HUMAN; ABCG8 PROTEIN, HUMAN; LIPOPROTEIN;

ABSORPTION; ADRENAL DISEASE; BILIARY EXCRETION; CARDIOVASCULAR DISEASE; CHOLELITHIASIS; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL STONE; CLINICAL FEATURE; CLINICAL TRIAL; DISORDERS OF LIPID AND LIPOPROTEIN METABOLISM; ENDOPLASMIC RETICULUM STRESS; ENZYMOLOGY; EXCRETION; GENE; GENE EXPRESSION; GENE MUTATION; HEART PROTECTION; HEPATOBILIARY SYSTEM; HUMAN; INSULIN RESISTANCE; INTESTINE ABSORPTION; METABOLIC DISORDER; METABOLIC SYNDROME X; NONHUMAN; OBESITY; PHYSIOLOGY; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SITOSTEROLEMIA; SUPPLEMENTATION; THROMBOCYTE DYSFUNCTION; ANIMAL; BLOOD; GENETICS; HEART DISEASE; METABOLISM;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; HEART DISEASES; HUMANS; LIPOPROTEINS; METABOLIC DISEASES; PHYTOSTEROLS; STEROLS;

EID: 66149106350     PISSN: 1752296X     EISSN: None     Source Type: Journal    
DOI: 10.1097/MED.0b013e3283292312     Document Type: Review

References (43)

1. Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol 2008; 61:588-594.
2. Kidambi S, Patel SB. Cholesterol and noncholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1- a review. Xenobiotica 2008; 38:1119-1139.
3. 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. This study provides a mechanism for platelet dysfunction sitosterolemia.
4. Mushtaq T, Wales JK, Wright NP. Adrenal insufficiency in phytosterolaemia. Eur J Endocrinol 2007; 157 (Suppl 1):S61-S65.
5. Tang W, Ma Y, Jia L, et al. Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8. J Lipid Res 2009; 50:293-300.
6. Lutjohann D, von Bergmann K, Sirah W, et al. Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, openlabel extension study. Int J Clin Pract 2008; 62:1499-1510. This study demonstrates that long-term treatment of sitosterolemia with ezetimibe is effective and safe.
7. Vrins C, Vink E, Vandenberghe KE, et al. The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux. FEBS Lett 2007; 581:4616-4620.
8. Wang J, Zhang DW, Lei Y, et al. Purification and reconstitution of sterol transfer by native mouse ABCG5 and ABCG8. Biochemistry 2008; 47:5194-5204.
9. Groen A, Kunne C, Jongsma G, et al. Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice. Gastroenterology 2008; 134:2091-2100.
10. Wang HH, Patel SB, Carey MC, Wang DQ. Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8(-/-) mice. Hepatology (Baltimore, Md) 2007; 45:998-1006.
11. Hamada T, Egashira N, Nishizono S, et al. Lymphatic absorption and deposition of various plant sterols in stroke-prone spontaneously hypertensive rats, a strain having a mutation in ATP binding cassette transporter G5. Lipids 2007; 42:241-248.
12. van der Velde AE, Vrins CL, van den Oever K, et al. Regulation of direct transintestinal cholesterol excretion in mice. Am J Physiol 2008; 295:G203-G208. This study demonstrates an active role for the intestine in the removal of cholesterol from the body.
13. Calpe-Berdiel L, Rotllan N, Fievet C, et al. Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8. J Lipid Res 2008; 49:1904-1911.
14. van der Veen JN, Havinga R, Bloks VW, et al. Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor alpha. J Lipid Res 2007; 48:337-347.
15. 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.
16. Galman C, Bonde Y, Matasconi M, et al. Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone. Gastroenterology 2008; 134:1127-1136.
17. Biddinger SB, Haas JT, Yu BB, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 2008; 14:778-782. This study provides a mechanistic link between hepatic insulin resistance and the risk of cholethiasis. This has substantial clinical implications for the regulation of G5G8 as well as bile acid synthesis in the development of cholesterol gallstones in obese and diabetic patients.
18. Sabeva NS, Rouse EJ, Graf GA. Defects in the leptin axis reduce abundance of the ABCG5-ABCG8 sterol transporter in liver. J Biol Chem 2007; 282:22397-22405.
19. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 2008; 29:42-61.
20. Gylling H, Hallikainen M, Kolehmainen M, et al. Cholesterol synthesis prevails over absorption in metabolic syndrome. Transl Res 2007; 149:310-316.
21. Smahelova A, Hyspler R, Haas T. Relation of cholesterol metabolism and noncholesterol sterols to insulin resistance. Physiol Res 2007; 56:749-755.
22. Scoggan KA, Gruber H, Chen Q, et al. Increased incorporation of dietary plant sterols and cholesterol correlates with decreased expression of hepatic and intestinal Abcg5 and Abcg8 in diabetic BB rats. J Nutr Biochem 2009; 20:177-186.
23. Santosa S, Demonty I, Lichtenstein AH, et al. Single nucleotide polymorphisms in ABCG5 and ABCG8 are associated with changes in cholesterol metabolism during weight loss. J Lipid Res 2007; 48:2607-2613.
24. 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.
25. 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.
26. Grunhage F, Acalovschi M, Tirziu S, et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology (Baltimore, Md) 2007; 46:793-801.
27. Chen ZC, Shin SJ, Kuo KK, et al. Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance. J Hum Genet 2008; 53:757-763.
28. Calpe-Berdiel L, Escola-Gil JC, Rotllan N, Blanco-Vaca F. Phytosterols do not change susceptibility to obesity, insulin resistance, and diabetes induced by a high-fat diet in mice. Metabolism 2008; 57:1497-1501.
29. John S, Sorokin AV, Thompson PD. Phytosterols and vascular disease. Curr Opin Lipidol 2007; 18:35-40.
30. Thompson GR, Grundy SM. History and development of plant sterol and stanol esters for cholesterol-lowering purposes. Am J Cardiol 2005; 96 (1A):3D-9D.
31. Houweling AH, Vanstone CA, Trautwein EA, et al. Baseline plasma plant sterol concentrations do not predict changes in serum lipids, C-reactive protein (CRP) and plasma plant sterols following intake of a plant sterolenriched food. Eur J Clin Nutr 2007. http://www.nature.com/ejcn/ journal/vaop/ncurrent/full/1602969a.html
32. Fransen HP, de Jong N, Wolfs M, et al. Customary use of plant sterol and plant stanol enriched margarine is associated with changes in serum plant sterol and stanol concentrations in humans. J Nutr 2007; 137:1301-1306.
33. de Jong A, Plat J, Lutjohann D, Mensink RP. Effects of long-term plant sterol or stanol ester consumption on lipid and lipoprotein metabolism in subjects on statin treatment. Br J Nutr 2008; 100:937-941.
34. 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.
35. Kassis AN, Vanstone CA, AbuMweis SS, Jones PJ. Efficacy of plant sterols is not influenced by dietary cholesterol intake in hypercholesterolemic individuals. Metabolism 2008; 57:339-346.
36. Grundy SM, Cleeman JI, Merz CN, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110:227-239.
37. Helske S, Miettinen T, Gylling H, et al. Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves. J Lipid Res 2008; 49:1511-1518.
38. Weingartner O, Lutjohann D, Ji S, et al. Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008; 51:1553-1561. This study demonstrates that phytosterol supplementation causes vascular dysfunction in mice. In addition, it demonstrates that inhibition of cholesterol absorption with ezetimibe is more effective at reducing atherosclerosis than phytosterols, despite similar effects on plasma cholesterol levels.
39. Plat J, de Jong A, Volger OL, et al. Preferential campesterol incorporation into various tissues in apolipoprotein E*3-Leiden mice consuming plant sterols or stanols. Metabolism 2008; 57:1241-1247.
40. Rubis B, Paszel A, Kaczmarek M, et al. Beneficial or harmful influence of phytosterols on human cells? Br J Nutr 2008; 100:1183-1191.
41. Moon DO, Kim MO, Choi YH, Kim GY. beta-Sitosterol induces G2/M arrest, endoreduplication, and apoptosis through the Bcl-2 and PI3K/Akt signaling pathways. Cancer Lett 2008; 264:181-191.
42. Awad AB, Barta SL, Fink CS, Bradford PG. beta-Sitosterol enhances tamoxifen effectiveness on breast cancer cells by affecting ceramide metabolism. Mol Nutr Food Res 2008; 52:419-426.
43. Koeijvoets KC, van der Net JB, Dallinga-Thie GM, et al. ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia. Atherosclerosis 2008.