Disodium ascorbyl phytostanol phosphate (FM-VP4), a modified phytostanol, is a highly active hypocholesterolaemic agent that affects the enterohepatic circulation of both cholesterol and bile acids in mice

British Journal of Nutrition

Volumn 103, Issue 2, 2010, Pages 153-160

  Mendez Gonzalez J ^a,b   Suren Castillo S ^a,c   Calpe Berdiel, L ^a,d   Rotllan, N ^a,e   Vazquez Carrera M ^e,f   Escola Gil J C ^a,e   Blanco Vaca, F ^a,b,e  

^a HOSPITAL DE LA SANTA CREU I SANT PAU   (Spain)

^b UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^c ISTANBUL UNIVERSITY   (Turkey)

^d LEIDEN UNIVERSITY   (Netherlands)

^e INSTITUTO DE SALUD CARLOS III   (Spain)

^f UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Bile acids; Cholesterol absorption; Liver; Mice; Phytostanols

Indexed keywords

ABC TRANSPORTER A1; BILE ACID; CAMPESTANOL; CHOLESTEROL; CHOLESTEROL 7ALPHA MONOOXYGENASE; DISODIUM ASCORBYL PHYTOSTANOL PHOSPHATE; FARNESOID X RECEPTOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYPOCHOLESTEROLEMIC AGENT; LIVER X RECEPTOR ALPHA; SCAVENGER RECEPTOR BI; SITOSTANOL; STEROL DERIVATIVE; TAUROCHOLIC ACID; TRITIUM; UNCLASSIFIED DRUG; FM VP4 COMPOUND; FM-VP4 COMPOUND; PHYTOSTEROL; RNA;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BILE ACID METABOLISM; C57BL 6 MOUSE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL LIVER LEVEL; CHOLESTEROL METABOLISM; CONTROLLED STUDY; DOWN REGULATION; DRUG MECHANISM; ENTEROHEPATIC CIRCULATION; FEMALE; GENE EXPRESSION REGULATION; IN VIVO STUDY; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PROTEIN EXPRESSION; UPREGULATION; ANIMAL; BLOOD; BODY WEIGHT; C57BL MOUSE; CALORIC INTAKE; DRUG EFFECT; GENETICS; HUMAN; INTESTINE ABSORPTION; ISOLATION AND PURIFICATION; LIVER; LIVER CIRCULATION; MALE; METABOLISM; PHYSIOLOGY; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SECRETION; SMALL INTESTINE;

MUS;

ANIMALS; BILE ACIDS AND SALTS; BODY WEIGHT; CHOLESTEROL; ENERGY INTAKE; HUMANS; INTESTINAL ABSORPTION; INTESTINE, SMALL; LIVER; LIVER CIRCULATION; MALE; MICE; MICE, INBRED C57BL; PHYTOSTEROLS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA;

EID: 75549084313     PISSN: 00071145     EISSN: 14752662     Source Type: Journal    
DOI: 10.1017/S0007114509991656     Document Type: Article

References (50)

1. Weihrauch JL & Gardner JM (1978) Sterol content of foods of plant origin. J Am Diet Assoc 73, 39-47.
2. Salen G, Ahrens EH Jr & Grundy SM (1970) Metabolism of b-sitosterol in man. J Clin Invest 49, 952-967.
3. 5-phytosterols and phytostanols in humans. Am J Physiol Endocrinol Metab 282, E911-E916.
4. Moghadasian MH & Frohlich JJ (1999) Effects of dietary phy-tosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence. Am J Med 107, 588-594.
5. Plat J, Kerckhoffs DA & Mensink RP (2000) Therapeutic potential of plant sterols and stanols. Curr Opin Lipidol 11, 571-576.
6. Ostlund RE Jr (2004) Phytosterols and cholesterol metabolism. Curr Opin Lipidol 15, 37-41.
7. Calpe-Berdiel L, Escola-Gil JC, Ribas V, et al. (2005) Changes in intestinal and liver global gene expression in response to a phytosterol-enriched diet. Atherosclerosis 181, 75-85.
8. Calpe-Berdiel L, Escola-Gil JC & Blanco-Vaca F (2008) New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis 203, 18-31.
9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285, 2486-2497.
10. Burnett JR & Huff MW (2006) Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolaemia. Expert Opin Investig Drugs 15, 1337-1351.
11. Wasan KM, Peteherych KD, Najafi S, et al. (2001) Assessing the plasma pharmacokinetics, tissue distribution, excretion and effects on cholesterol pharmacokinetics of a novel hydrophilic compound, FM-VP4, following administration to rats. J Pharm Pharm Sci 4, 207-216.
12. Wasan KM, Zamfir C, Pritchard PH, et al. (2003) Influence of phytostanol phosphoryl ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. J Pharm Sci 92, 281-288.
13. Ebine N, Jia X, Demonty I, et al. (2005) Effects of a water-soluble phytostanol ester on plasma cholesterol levels and red blood cell fragility in hamsters. Lipids 40, 175-180.
14. Lukic T, Wasan KM, Zamfir D, et al. (2003) Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice. Metabolism 52, 425-431.
15. Wasan KM, Najafi S, Peteherych KD, et al. (2001) Effects of a novel hydrophilic phytostanol analog on plasma lipid concentrations in gerbils. J Pharm Sci 90, 1795-1799.
16. Wasan KM, Najafi S, Wong J, et al. (2001) Assessing plasma lipid levels, body weight, and hepatic and renal toxicity following chronic oral administration of a water soluble phytostanol compound, FM-VP4, to gerbils. J Pharm Pharm Sci 4, 228-234.
17. Vissers MN, Trip MD, Pritchard PH, et al. (2008) Efficacy and safety of disodium ascorbyl phytostanol phosphates in men with moderate dyslipidemia. Eur J Clin Pharmacol 64, 649-650.
18. Looije NA, Risovic V, Stewart DJ, et al. (2005) Disodium ascorbyl phytostanyl phosphates (FM-VP4) reduces plasma cholesterol concentration, body weight and abdominal fat gain within a dietary-induced obese mouse model. J Pharm Pharm Sci 8, 400-408.
19. Thornton SJ, Warburton C, Wasan KM, et al. (2007) Treatment with a cholesterol absorption inhibitor (FM-VP4) reduces body mass and adipose accumulation in developing and pre-obese mice. Drug Dev Ind Pharm 33, 1058-1069.
20. Ikeda I, Tanabe Y & Sugano M (1989) Effects of sitosterol and sitostanol on micellar solubility of cholesterol. J Nutr Sci Vitaminol (Tokyo) 35, 361-369.
21. Plat J & Mensink RP (2002) Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women. FASEB J 16, 258-260.
22. Volger OL, van der Boom H, de Wit EC, et al. (2001) Dietary plant stanol esters reduce VLDL cholesterol secretion and bile saturation in apolipoprotein E*3-Leiden transgenic mice. Arterioscler Thromb Vasc Biol 21, 1046-1052.
23. Ntanios FY & Jones PJ (1999) Dietary sitostanol reciprocally influences cholesterol absorption and biosynthesis in hamsters and rabbits. Atherosclerosis 143, 341-351.
24. Xu Z, Le K & Moghadasian MH (2007) Long-term phytosterol treatment alters gene expression in the liver of apo E-deficient mice. J Nutr Biochem 19, 545-554.
25. Shefer S, Salen G, Nguyen L, et al. (1988) Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 a-hydroxylase. J Clin Invest 82, 1833-1839.
26. Yu L, von Bergmann K, Lutjohann D, et al. (2004) Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J Lipid Res 45, 301-307.
27. Yang C, Yu L, Li W, et al. (2004) Disruption of cholesterol homeostasis by plant sterols. J Clin Invest 114, 813-822.
28. Nguyen LB, Shefer S, Salen G, et al. (1990) A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J Clin Invest 86, 923-931.
29. Gylling H, Puska P, Vartiainen E, et al. (1999) Serum sterols during stanol ester feeding in a mildly hypercholesterolemic population. J Lipid Res 40, 593-600.
30. Normen L, Dutta P, Lia A, et al. (2000) Soy sterol esters and b-sitostanol ester as inhibitors of cholesterol absorption in human small bowel. Am J Clin Nutr 71, 908-913.
31. Weststrate JA, Ayesh R, Bauer-Plank C, et al. (1999) Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enriched margarine. Food Chem Toxicol 37, 1063-1071.
32. Plosch T, Kruit JK, Bloks VW, et al. (2006) Reduction of cholesterol absorption by dietary plant sterols and stanols in mice is independent of the ABCG5/8 transporter. J Nutr 136, 2135-2140.
33. Ng AW, Lukic T, Pritchard PH, et al. (2004) Development and characterization of liposomal disodium ascorbyl phytostanyl phosphates (FM-VP4). Drug Dev Ind Pharm 30, 739-758.
34. National Research Council (1996) Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press.
35. Ribas V, Palomer X, Roglans N, et al. (2005) Paradoxical exacerbation of combined hyperlipidemia in human apolipopro-tein A-II transgenic mice treated with fenofibrate. Biochim Biophys Acta 1737, 130-137.
36. Repa JJ, Dietschy JM & Turley SD (2002) Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte. J Lipid Res 43, 1864-1874.
37. Calpe-Berdiel L, Escola-Gil JC & Blanco-Vaca F (2006) Phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of ATP-binding cassette transporter A1. Br J Nutr 95, 618-622.
38. Yu L, Li-Hawkins J, Hammer RE, et al. (2002) Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 110, 671-680.
39. Plosch T, Kok T, Bloks VW, et al. (2002) Increased hepatobili-ary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J Biol Chem 277, 33870-33877.
40. Wilund KR, Yu L, Xu F, et al. (2004) High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholester-olemia and atherosclerosis in Ldlr 2/2 mice. J Lipid Res 45, 1429-1436.
41. Kozarsky KF, Donahee MH, Rigotti A, et al. (1997) Over-expression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 387, 414-417.
42. Kozarsky KF, Donahee MH, Glick JM, et al. (2000) Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol 20, 721-727.
43. Naik SU, Wang X, Da Silva JS, et al. (2006) Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 113, 90-97.
44. Field FJ, Born E & Mathur SN (2004) Stanol esters decrease plasma cholesterol independently of intestinal ABC sterol transporters and Niemann-Pick C1-like 1 protein gene expression. J Lipid Res 45, 2252-2259.
45. Chiang JY (2002) Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev 23, 443-463.
46. Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72, 137-174.
47. Chiang JY (2004) Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol 40, 539-551.
48. Stedman C, Liddle C, Coulter S, et al. (2006) Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci USA 103, 11323-11328.
49. Alrefai WA & Gill RK (2007) Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 24, 1803-1823.
50. Teng S & Piquette-Miller M (2007) Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis. Br J Pharmacol 151, 367-376.