Phytosterol Feeding Causes Toxicity in ABCG5/G8 Knockout Mice

Plant sterols, or phytosterols, are very similar in structure to cholesterol and are abundant in typical diets. The reason for poor absorption of plant sterols by the body is still unknown. Mutations in the ABC transporters G5 and G8 are known to cause an accumulation of plant sterols in blood and tissues (sitosterolemia). To determine the significance of phytosterol exclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterols. The high-phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wild-type mice. ABCG5/G8 knockout mice died prematurely and developed a phenotype that included high levels of plant sterols in many tissues, liver abnormalities, and severe cardiac lesions. This study is the first to report such toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice. We believe these new data support the conclusion that plant sterols are excluded from the body because they are toxic when present at high levels. Plant sterols, or phytosterols, are very similar in structure to cholesterol and are abundant in typical diets. The reason for poor absorption of plant sterols by the body is still unknown. Mutations in the ABC transporters G5 and G8 are known to cause an accumulation of plant sterols in blood and tissues (sitosterolemia). To determine the significance of phytosterol exclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterols. The high-phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wild-type mice. ABCG5/G8 knockout mice died prematurely and developed a phenotype that included high levels of plant sterols in many tissues, liver abnormalities, and severe cardiac lesions. This study is the first to report such toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice. We believe these new data support the conclusion that plant sterols are excluded from the body because they are toxic when present at high levels. One of the longstanding mysteries of sterol metabolism is the need for discrimination between plant sterols (or phytosterols) and cholesterol. It has long been observed that although a typical diet generally contains similar amounts of cholesterol and phytosterols, intestinal cholesterol absorption rates are 40% to 60%, whereas phytosterols are mostly excluded from the body due to intestinal absorption rates of less than 5%.1Weihrauch J.L. Gardner J.M. Sterol content of foods of plant origin.J Am Diet Assoc. 1978; 73: 39-47PubMed Google Scholar, 2Schoenheimer R. New contributions in sterol metabolism.Science. 1931; 74: 579-584Crossref PubMed Scopus (44) Google Scholar The discrimination against phytosterols has a basis in chemical structure. Campesterol, with a single-carbon side chain at carbon 24, typically has a plasma concentration 500 times less than cholesterol; whereas, the concentration of sitosterol, with a 2-carbon side chain at carbon 24, is about 20,000 times lower than cholesterol.3Ostlund Jr., R.E. McGill J.B. Zeng C.M. Covey D.F. Stearns J. Stenson W.F. Spilburg C.A. Gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans.Am J Physiol Endocrinol Metab. 2002; 282: E911-E916Crossref PubMed Scopus (226) Google Scholar The need for discrimination among sterols is not fully understood. In 1974, Bhattacharyya and Connor4Bhattacharyya A.K. Connor W.E. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters.J Clin Invest. 1974; 53: 1033-1043Crossref PubMed Scopus (464) Google Scholar described a new lipid storage disease, termed β-sitosterolemia, in two sisters with plant sterol accumulation in blood and tissues. Subsequently, several other patients with sitosterolemia have been identified.5Lee M.H. Lu K. Patel S.B. Genetic basis of sitosterolemia.Curr Opin Lipidol. 2001; 12: 141-149Crossref PubMed Scopus (168) Google Scholar Patients accumulate plant sterols in many tissues and often present with tendinous and cutaneous xanthomas and hypercholesterolemia.5Lee M.H. Lu K. Patel S.B. Genetic basis of sitosterolemia.Curr Opin Lipidol. 2001; 12: 141-149Crossref PubMed Scopus (168) Google Scholar, 6Hidaka H. Nakamura T. Aoki T. Kojima H. Nakajima Y. Kosugi K. Hatanaka I. Harada M. Kobayashi M. Tamura A. Fujii T. Shigeta Y. Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.J Lipid Res. 1990; 31: 881-888PubMed Google Scholar There are also indications that plasma plant sterol accumulation has negative effects on platelet biology.7Rees D.C. Iolascon A. Carella M. O’marcaigh A.S. Kendra J.R. Jowitt S.N. Wales J.K. Vora A. Makris M. Manning N. Nicolaou A. Fisher J. Mann A. Machin S.J. Clayton P.T. Gasparini P. Stewart G.W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.Br J Haematol. 2005; 130: 297-309Crossref PubMed Scopus (113) Google Scholar Elimination of plant sterols from their diet is an effective treatment for patients.7Rees D.C. Iolascon A. Carella M. O’marcaigh A.S. Kendra J.R. Jowitt S.N. Wales J.K. Vora A. Makris M. Manning N. Nicolaou A. Fisher J. Mann A. Machin S.J. Clayton P.T. Gasparini P. Stewart G.W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.Br J Haematol. 2005; 130: 297-309Crossref PubMed Scopus (113) Google Scholar, 8Belamarich P.F. Deckelbaum R.J. Starc T.J. Dobrin B.E. Tint G.S. Salen G. Response to diet and cholestyramine in a patient with sitosterolemia.Pediatrics. 1990; 86: 977-981PubMed Google Scholar Subsequent work has identified genetic mutations to the heterodimeric ABC transporters, ABCG5 and ABCG8, as the cause of sitosterolemia.9Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1361) Google Scholar, 10Lee M.H. Lu K. Hazard S. Yu H. Shulenin S. Hidaka H. Kojima H. Allikmets R. Sakuma N. Pegoraro R. Srivastava A.K. Salen G. Dean M. Patel S.B. Identification of a gene. ABCG5, important in the regulation of dietary cholesterol absorption.Nat Genet. 2001; 27: 79-83Crossref PubMed Scopus (0) Google Scholar, 11Lu K. Lee M.H. Hazard S. Brooks-Wilson A. Hidaka H. Kojima H. Ose L. Stalenhoef A.F. Mietinnen T. Bjorkhem I. Bruckert E. Pandya A. Brewer Jr., H.B. Salen G. Dean M. Srivastava A. Patel S.B. 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. 2001; 69: 278-290Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Both ABCG5 and ABCG8 must be expressed for their cotransport from the endoplasmic reticulum to the cell surface.12Graf G.A. Li W.P. Gerard R.D. Gelissen I. White A. Cohen J.C. Hobbs H.H. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface.J Clin Invest. 2002; 110: 659-669Crossref PubMed Scopus (299) Google Scholar, 13Graf G.A. Yu L. Li W.P. Gerard R. Tuma P.L. Cohen J.C. Hobbs H.H. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion.J Biol Chem. 2003; 278: 48275-48282Crossref PubMed Scopus (371) Google Scholar Therefore, mutations to either or both of these proteins can result in a loss of functionality. These proteins are mainly expressed in the intestine and liver on the apical surface of enterocytes and hepatocytes.12Graf G.A. Li W.P. Gerard R.D. Gelissen I. White A. Cohen J.C. Hobbs H.H. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface.J Clin Invest. 2002; 110: 659-669Crossref PubMed Scopus (299) Google Scholar, 14Repa J.J. Berge K.E. Pomajzl C. Richardson J.A. Hobbs H. Mangelsdorf D.J. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta.J Biol Chem. 2002; 277: 18793-18800Crossref PubMed Scopus (689) Google Scholar They apparently function to transport cholesterol and phytosterols into bile in the liver and into the lumen of the small intestine,15Yu L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar although their full functional significance is yet to be determined. The identification of ABCG5 and ABCG8 as important players in sterol transport has led to the discovery and creation of several mouse models that lack one or both of the proteins. By genetic manipulations, ABCG5 single-knockout (KO), ABCG8 single-KO, and ABCG5/G8 double-KO mice have been created. Additionally, one mouse model with a spontaneous mutation of ABCG5 has been previously described in the literature. The trac mutant mouse, which develops thrombocytopenia and cardiomyopathy, has a spontaneous point mutation at base 1435 of Abcg5 that results in a premature stop codon.16Chase T.H. Lyons B.L. Bronson R.T. Foreman O. Donahue L.R. Burzenski L.M. Gott B. Lane P. Harris B. Ceglarek U. Thiery J. Wittenburg H. Thon J.N. Italiano Jr., J.E. Johnson K.R. Shultz L.D. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia.Blood. 2010; 115: 1267-1276Crossref PubMed Scopus (38) Google Scholar The trac mutant mice and the genetically modified KO mice have subtle differences among the models, but all have the fundamental accumulation of plant sterols in plasma and tissues.15Yu L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 17Plosch T. Bloks V.W. Terasawa Y. Berdy S. Siegler K. Van Der Sluijs F. Kema I.P. Groen A.K. Shan B. Kuipers F. Schwarz M. Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor.Gastroenterology. 2004; 126: 290-300Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 18Klett E.L. Lu K. Kosters A. Vink E. Lee M.H. Altenburg M. Shefer S. Batta A.K. Yu H. Chen J. Klein R. Looije N. Oude-Elferink R. Groen A.K. Maeda N. Salen G. Patel S.B. A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.BMC Med. 2004; 2: 5Crossref PubMed Scopus (123) Google Scholar, 19Yu L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar, J.K. Bloks V.W. N. G. Kema I.P. E. Kuipers F. Plant sterols cause macrothrombocytopenia in a mouse model of Biol Chem. PubMed Scopus Google Scholar This phenotype is similar to that of human patients with ABCG5 and ABCG8 an role in plant sterols from the body, although the function is not understood. To determine the significance of phytosterol exclusion from the body, wild-type and ABCG5/G8 KO mice fed a diet with The high-phytosterol diet had no adverse effects on but was extremely toxic to ABCG5/G8 KO mice. levels of plant sterol accumulation cause premature cardiac liver and which have not been previously in ABCG5/G8 KO mice have been described L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar and ABCG5/G8 KO mice on a of and in a in in a with a The mice fed a diet the of the high-phytosterol diet and had to to of and ABCG5/G8 KO mice fed a of as diet phytosterols and cholesterol for The diet was at the Diet the by the and at blood was from mice that had been fed the for with and either in or in for To determine plasma cholesterol and phytosterol of plasma was into a of and in from plasma and with an in was as an of cholesterol and phytosterol of was into a of in at sterol was for all by as described R.E. A.K. with and the to cholesterol from Biol Chem. 2003; 278: PubMed Scopus Google Scholar a blood was the of a high-phytosterol for blood of and plasma to by by of blood into and to of of liver and into of and was to the and of was and was and of to the gene was in and for gene of and on an the for for for for for for and of gene was to of a gene or to for and expressed as in a new in for at for at and with and von liver for in by in and with by in a by a To determine cell in a single for liver cell was to the of in To cardiac of the was and from the of and to the are expressed as the of differences was for of by of or A was fed a diet in plant sterols, mice a whereas ABCG5/G8 KO mice generally poor by and and that mice the of the high-phytosterol whereas the ABCG5/G8 KO mice not to their This phenotype was not in ABCG5/G8 KO mice fed a diet an of cholesterol and This that these effects not caused by a accumulation of sterols in the body, but caused by the accumulation of plant sterols. that by the ABCG5/G8 KO mice fed the high-phytosterol diet had a high of liver and in ABCG5/G8 KO mice to mice. This into of for liver and By was no in the or of of the or of ABCG5/G8 KO mice and To the of the ABCG5/G8 KO to be in ABCG5/G8 KO mice at all in to in mice that in the ABCG5/G8 KO mice no in or when to mice the dietary not of liver from and ABCG5/G8 KO mice with by an ABCG5/G8 KO mouse and had and and and cell of in these a in the of present in ABCG5/G8 KO mouse as to This in was also by a of to KO the in a in the was by levels in ABCG5/G8 KO mice mouse and and gene metabolism metabolism metabolism gene was from tissues. was to or and expressed as as by in a new was from tissues. was to or and expressed as as by To the effects of phytosterol accumulation on lipid and bile a of genes and levels by previously by Yu L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar ABCG5/G8 KO mice had a in when to mice. to levels included an in and a in ATP-binding cassette levels of ATP-binding cassette protein sterol protein and cholesterol not between and ABCG5/G8 KO mice. data that in these phytosterols are not into bile as had been to in E. J. Bjorkhem I. of bile from plant sterols in the Biol Chem. 1990; Full Text PDF PubMed Google Scholar and I. to be to determine the phytosterols in lipid and bile ABCG5/G8 KO mice accumulate plant sterols in liver and plasma on a diet with phytosterol L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar we the sterol several tissues. and tissues from ABCG5/G8 KO mice all have levels of phytosterols, to but in the of sterol the of A and a phytosterols for a of the sterol amounts in the tissues of ABCG5/G8 KO mice. In sterol as high as phytosterol in the liver plant tissues had a of sterol from to phytosterol previously in ABCG5/G8 KO L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar plant sterols not accumulate in the to the as in other tissues A and plasma sterol concentration was in ABCG5/G8 KO mice to mice This was due to a plasma phytosterol concentration of which in of plasma sterol to be plant sterol in ABCG5/G8 KO mice previously in ABCG5/G8 KO plasma cholesterol in the ABCG5/G8 KO mice as to L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar and sterol also because macrothrombocytopenia has been observed in both human patients with sitosterolemia and in ABCG5/G8 KO D.C. Iolascon A. Carella M. O’marcaigh A.S. Kendra J.R. Jowitt S.N. Wales J.K. Vora A. Makris M. Manning N. Nicolaou A. Fisher J. Mann A. Machin S.J. Clayton P.T. Gasparini P. Stewart G.W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.Br J Haematol. 2005; 130: 297-309Crossref PubMed Scopus (113) Google Scholar, J.K. Bloks V.W. N. G. Kema I.P. E. Kuipers F. Plant sterols cause macrothrombocytopenia in a mouse model of Biol Chem. PubMed Scopus Google Scholar the diet for ABCG5/G8 KO mice had lower to that of mice which at and Additionally, the sterol of ABCG5/G8 KO which at phytosterol at to phytosterol the dietary The liver and both an important role in from the the liver and and the of ABCG5/G8 KO mice a of plant sterol that their was to the of several and genes in These genes on by I. M. J. Kuipers F. T.J. Van M. cholesterol levels are an important for the of 2005; Full Text Full Text PDF PubMed Scopus Google Scholar the and the genes in the of These genes included A and and gene was to and between and ABCG5/G8 KO mice on the high-phytosterol with the of and of and with was in mice ABCG5/G8 an cardiac phenotype was in the ABCG5/G8 KO mice. of the ABCG5/G8 KO mice had and of in the To these cardiac in and with von and that the not have from ABCG5/G8 KO had loss with by and von and the of and in these cardiac of the a in the of in ABCG5/G8 KO mice to mice. was of the was in ABCG5/G8 KO mouse but less than of the was in mouse This study for the first the that when phytosterols accumulate at high levels in the ABCG5/G8 KO which plant sterols, to and and prematurely when fed a high-phytosterol This phenotype is to plant sterol as we not of poor in ABCG5/G8 KO mice fed a high cholesterol side effects have not been in other ABCG5/G8 double-KO mice fed lower levels of L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 19Yu L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar In with other L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 19Yu L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar and the plant sterol that in ABCG5/G8 KO mice that fed the plant Plant sterols to very high levels in the tissues of ABCG5/G8 KO mice. of all sterols in mice and from to of sterols in and These are than the in ABCG5/G8 KO mice fed a L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar a plasma phytosterol in ABCG5/G8 KO mice to L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc Natl Acad Sci U S A. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 19Yu L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar the high-phytosterol diet we plasma phytosterol levels times that The levels of phytosterol accumulation caused in several tissues. ABCG5/G8 KO mice had and liver ABCG5/G8 KO mice developed and with loss of By with was in the trac mutant mouse, but cardiac not T.H. Lyons B.L. Bronson R.T. Foreman O. Donahue L.R. Burzenski L.M. Gott B. Lane P. Harris B. Ceglarek U. Thiery J. Wittenburg H. Thon J.N. Italiano Jr., J.E. Johnson K.R. Shultz L.D. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia.Blood. 2010; 115: 1267-1276Crossref PubMed Scopus (38) Google Scholar The trac mutant mice have a spontaneous mutation in ABCG5 that to accumulate plant sterols. mutation to be with a less severe phenotype than in ABCG5/G8 KO mice. The trac mutant not fed the high-phytosterol mutant mice and have a of on a T.H. Lyons B.L. Bronson R.T. Foreman O. Donahue L.R. Burzenski L.M. Gott B. Lane P. Harris B. Ceglarek U. Thiery J. Wittenburg H. Thon J.N. Italiano Jr., J.E. Johnson K.R. Shultz L.D. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia.Blood. 2010; 115: 1267-1276Crossref PubMed Scopus (38) Google Scholar By ABCG5/G8 KO mice died as as of when fed the high-phytosterol diet of diet of poor in ABCG5/G8 KO such as and failure to not in trac mutant mice. The differences between these mouse models be to the of phytosterols that accumulate in the mutant mice have plasma phytosterol of which in between and ABCG5/G8 KO mice and ABCG5/G8 KO mice. This support the that the of of phytosterols on the of accumulation in the in both and mouse models have macrothrombocytopenia as a of D.C. Iolascon A. Carella M. O’marcaigh A.S. Kendra J.R. Jowitt S.N. Wales J.K. Vora A. Makris M. Manning N. Nicolaou A. Fisher J. Mann A. Machin S.J. Clayton P.T. Gasparini P. Stewart G.W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.Br J Haematol. 2005; 130: 297-309Crossref PubMed Scopus (113) Google Scholar, J.K. Bloks V.W. N. G. Kema I.P. E. Kuipers F. Plant sterols cause macrothrombocytopenia in a mouse model of Biol Chem. PubMed Scopus Google Scholar The plasma phenotype of ABCG5/G8 KO mice fed a high-phytosterol diet was with phytosterol content by and in as as of diet and levels in ABCG5/G8 KO mice. These data that the is which be an to blood have not of phytosterols in the of ABCG5/G8 KO L. von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. sterol accumulation in Lipid Res. 2004; PubMed Scopus Google Scholar Lutjohann D. K. T. T. J. von Bergmann K. Groen A.K. Kuipers F. M. plant sterols accumulate in the PubMed Scopus Google Scholar a but of phytosterols, in the of ABCG5 or ABCG8 KO mice. In we also but amounts of plant sterols that in the of ABCG5/G8 KO mice fed a high-phytosterol These levels of phytosterols in the to the amounts that in other tissues. The of study are in to dietary phytosterol which is to the of disease T. J. Y. L. J. The effects of on blood lipid a with J Clin Google Scholar, R. Plant as cholesterol a of Res. Google Scholar Plant sterols are to plasma cholesterol by cholesterol S. N. The and absorption of cholesterol and A 282: Scopus Google Scholar, P. M. T. R. and of plant and sterols in the of blood cholesterol Clin 2003; Google Scholar are to plant sterols from the body and the and foods to be as as In several of with ABCG5/G8 that have been high of plant sterols, have been no of R. New contributions in sterol metabolism.Science. 1931; 74: 579-584Crossref PubMed Scopus (44) Google Scholar still about the of dietary phytosterol their effects on in study that an extremely high concentration of phytosterols in plasma and tissues is and This phenotype to on the of phytosterols that The of ABCG5/G8 in an to full against dietary phytosterol and is no that cause levels of phytosterols to to toxic levels. dietary with phytosterols for the also into the need of the body to between plant sterols and cholesterol. We have for the first that high levels of plant sterol accumulation cause premature cardiac liver and These to accumulation of high levels of phytosterols that be into bile for storage in lipid The sterol results in accumulation in with of In data that the role of ABCG5/G8 in phytosterol exclusion from the body is to from the toxic effects of plant sterols. with fed a diet of for ABCG5/G8 KO with

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