Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice

The farnesoid X receptor (FXR) is a bile acid-activated transcription factor that regulates the expression of genes critical for bile acid and lipid homeostasis. This study was undertaken to investigate the pathological consequences of the loss of FXR function on the risk and severity of atherosclerosis. For this purpose, FXR-deficient (FXR−/−) mice were crossed with apolipoprotein E-deficient (ApoE−/−) mice to generate FXR−/−ApoE−/− mice. Challenging these mice with a high-fat, high-cholesterol (HF/HC) diet resulted in reduced weight gain and decreased survival compared with wild-type, FXR−/−, and ApoE−/− mice. FXR−/−ApoE−/− mice also had the highest total plasma lipids and the most atherogenic lipoprotein profile. Livers from FXR−/− and FXR−/− ApoE−/− mice exhibited marked lipid accumulation, focal necrosis (accompanied by increased levels of plasma aspartate aminotransferase), and increased inflammatory gene expression. Measurement of en face lesion area of HF/HC-challenged mice revealed that although FXR−/− mice did not develop atherosclerosis, FXR−/−ApoE−/− mice had approximately double the lesion area compared with ApoE−/− mice.In conclusion, loss of FXR function is associated with decreased survival, increased severity of defects in lipid metabolism, and more extensive aortic plaque formation in a mouse model of atherosclerotic disease. The farnesoid X receptor (FXR) is a bile acid-activated transcription factor that regulates the expression of genes critical for bile acid and lipid homeostasis. This study was undertaken to investigate the pathological consequences of the loss of FXR function on the risk and severity of atherosclerosis. For this purpose, FXR-deficient (FXR−/−) mice were crossed with apolipoprotein E-deficient (ApoE−/−) mice to generate FXR−/−ApoE−/− mice. Challenging these mice with a high-fat, high-cholesterol (HF/HC) diet resulted in reduced weight gain and decreased survival compared with wild-type, FXR−/−, and ApoE−/− mice. FXR−/−ApoE−/− mice also had the highest total plasma lipids and the most atherogenic lipoprotein profile. Livers from FXR−/− and FXR−/− ApoE−/− mice exhibited marked lipid accumulation, focal necrosis (accompanied by increased levels of plasma aspartate aminotransferase), and increased inflammatory gene expression. Measurement of en face lesion area of HF/HC-challenged mice revealed that although FXR−/− mice did not develop atherosclerosis, FXR−/−ApoE−/− mice had approximately double the lesion area compared with ApoE−/− mice. In conclusion, loss of FXR function is associated with decreased survival, increased severity of defects in lipid metabolism, and more extensive aortic plaque formation in a mouse model of atherosclerotic disease. Dyslipidemia, characterized by low levels of HDL and high levels of LDL, is a known risk factor for the development of atherosclerosis. An important early event in this disease process is the deposition of lipid-filled plaques in the walls of arteries. Plaque formation is initiated when arterial wall macrophages accumulate modified LDL and initiate a chronic inflammatory state. Over time, this inflammatory state can lead to thickening of the arterial wall, fibrosis, and eventually rupture of the plaque, thrombosis, and occlusion of normal blood flow (1Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Google Scholar). The current regimen of pharmacological therapies for the treatment of cardiovascular disease remains incomplete, despite the fact that cardiovascular disease (characterized by atherosclerosis) remains the leading cause of death in Western societies (2Canada, S. 2002. Leading Causes of Death 2002. (Statistics Canada, Ottawa, Ontario).Google Scholar, 3Kung Hoyert, D. L. H-C. Smith B.L. Deaths: preliminary data for 2003. In National Vital Statistics Reports.National Center for Health Statistics, Hyattsville, MD. 2005; 53: 1-23Google Scholar). Nuclear receptors are ligand-activated transcription factors that regulate many physiological and developmental processes, such as reproduction, metabolism, and cellular differentiation. This function is achieved by modulating the expression of target genes through binding to specific response elements in the promoter regions of these genes, leading to the recruitment of coactivators or corepressors that induce or repress the target gene, respectively (4Francis G.A. Fayard E. Picard F. Auwerx J. Nuclear receptors and the control of metabolism.Annu. Rev. Physiol. 2003; 65: 261-311Google Scholar). A number of nuclear receptors, including the liver X receptors and peroxisome proliferator-activated receptors, have important regulatory roles in lipid homeostasis (5Tontonoz P. Mangelsdorf D.J. Liver X receptor signaling pathways in cardiovascular disease.Mol. Endocrinol. 2003; 17: 985-993Google Scholar, 6Lee C.H. Olson P. Evans R.M. Minireview. Lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors.Endocrinology. 2003; 144: 2201-2207Google Scholar, 7Barish G.D. Evans R.M. PPARs and LXRs: atherosclerosis goes nuclear.Trends Endocrinol. Metab. 2004; 15: 158-165Google Scholar, 8Chinetti-Gbaguidi G. Fruchart J.C. Staels B. Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy.Curr. Opin. Pharmacol. 2005; 5: 177-183Google Scholar). Consequently, a great deal of research has been devoted to the selective modulation of these receptors as a novel therapeutic approach to the prevention and treatment of atherosclerosis (9Hanniman E.A. Sinal C.J. Nuclear receptors: novel therapeutic targets for the treatment and prevention of atherosclerosis.Drug Discovery Today: Therapeutic Strategies. 2004; 1: 155-161Google Scholar, 10Castrillo A. Tontonoz P. PPARs in atherosclerosis: the clot thickens.J. Clin. Invest. 2004; 114: 1538-1540Google Scholar, 11Berger J.P. Akiyama T.E. Meinke P.T. PPARs: therapeutic targets for metabolic disease.Trends Pharmacol. Sci. 2005; 26: 244-251Google Scholar). Excess cholesterol is transported from peripheral tissues to the liver by HDL-mediated reverse cholesterol transport (RCT). Once in the liver, cholesterol can be secreted into the bile either directly or after conversion to bile acids. The farnesoid X receptor (FXR) is a nuclear receptor that is activated by binding to bile acids and functions primarily as a bile acid sensor in the liver to induce and repress genes involved in bile acid export (bile salt export pump) and synthesis (cytochrome P450 7A1), respectively (12Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. et al.A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.Mol. Cell. 2000; 6: 517-526Google Scholar, 13Schuetz E.G. Strom S. Yasuda K. Lecureur V. Assem M. Brimer C. Lamba J. Kim R.B. Ramachandran V. Komoroski B.J. et al.Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450.J. Biol. Chem. 2001; 276: 39411-39418Google Scholar). This conversion of cholesterol to bile acids and subsequent efflux to the bile is a quantitatively important contributor to RCT and by extension is also important for the prevention of atherosclerosis. Beyond this function, accumulating evidence strongly supports an expanded role for FXR in the regulation of systemic lipid homeostasis. For example, FXR activates the expression of the genes encoding apolipoprotein C-II (apoC-II) and the LDL receptor (14Kast H.R. Nguyen C.M. Sinal C.J. Jones S.A. Laffitte B.A. Reue K. Gonzalez F.J. Willson T.M. Edwards P.A. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.Mol. Endocrinol. 2001; 15: 1720-1728Google Scholar, 15Sirvent A. Claudel T. Martin G. Brozek J. Kosykh V. Darteil R. Hum D.W. Fruchart J.C. Staels B. The farnesoid X receptor induces very low density lipoprotein receptor gene expression.FEBS Lett. 2004; 566: 173-177Google Scholar) and represses the expression of the genes encoding apoA-I and apoC-III as well as hepatic lipase (16Claudel T. Sturm E. Duez H. Torra I.P. Sirvent A. Kosykh V. Fruchart J.C. Dallongeville J. Hum D.W. Kuipers F. et al.Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element.J. Clin. Invest. 2002; 109: 961-971Google Scholar, 17Claudel T. Inoue Y. Barbier O. Duran-Sandoval D. Kosykh V. Fruchart J. Fruchart J.C. Gonzalez F.J. Staels B. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.Gastroenterology. 2003; 125: 544-555Google Scholar). More recently, FXR has also been linked to the regulation of carbohydrate metabolism (18Stayrook K.R. Bramlett K.S. Savkur R.S. Ficorilli J. Cook T. Christe M.E. Michael L.F. Burris T.P. Regulation of carbohydrate metabolism by the farnesoid X receptor.Endocrinology. 2005; 146: 984-991Google Scholar, 19Duran-Sandoval D. Mautino G. Martin G. Percevault F. Barbier O. Fruchart J.C. Kuipers F. Staels B. Glucose regulates the expression of the farnesoid X receptor in liver.Diabetes. 2004; 53: 890-898Google Scholar, 20Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition.J. Biol. Chem. 2005; 280: 29971-29979Google Scholar). Together, these data indicate a broad regulatory role for FXR in systemic energy metabolism. Given that FXR activation is linked to the repression of hepatic bile acid synthesis, agonists of this receptor would be expected to impair RCT and hepatic cholesterol elimination. Consistent with this, treatment of wild-type but not FXR−/− mice with the FXR antagonist guggulsterone has been reported to hepatic cholesterol J. C. J. S. The guggulsterone as an antagonist of the bile acid Endocrinol. 2002; Scholar, P. Y. Gonzalez F.J. Mangelsdorf D.J. Moore D.D. A that cholesterol as an antagonist for 2002; Scholar). FXR−/− mice increased blood triglyceride and cholesterol levels as well as increased of lipids in the liver, despite increased of bile acids and cholesterol G. G. Gonzalez F.J. Sinal C.J. The farnesoid is an of cholesterol Biol. Chem. 2003; Scholar, C.J. M. M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Scholar). FXR agonists have been to a of blood triglyceride in (14Kast H.R. Nguyen C.M. Sinal C.J. Jones S.A. Laffitte B.A. Reue K. Gonzalez F.J. Willson T.M. Edwards P.A. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.Mol. Endocrinol. 2001; 15: 1720-1728Google Scholar, 17Claudel T. Inoue Y. Barbier O. Duran-Sandoval D. Kosykh V. Fruchart J. Fruchart J.C. Gonzalez F.J. Staels B. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.Gastroenterology. 2003; 125: 544-555Google Scholar, D.J. G. Moore L.B. Wilson J.G. Lewis M.C. et of a for the nuclear receptor Chem. 2000; Scholar). This study was undertaken to and the pathological consequences of the loss of FXR function on lipid homeostasis and atherosclerotic The of this study indicate that of the FXR gene to more atherosclerosis in an model of this disease and the evidence linking this receptor to the risk and severity of cardiovascular disease. ApoE−/− mice were from FXR−/− mice to were crossed with ApoE−/− mice to the FXR−/−ApoE−/− mice. The of mice in this study was to mice were on either on the or a high-fat, high-cholesterol (HF/HC) diet and cholesterol for were and was the were on a and and were the in with on was after a and for was and cholesterol levels were and in and to the were after of the plasma with and an were by the in and a of were a was a of plasma from plasma and of lipid of the subsequent were as G. Martin P. J. B. S. lipase the selective of in Lipid 2000; Scholar). of and in the LDL, and HDL and were as C.J. M. M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Scholar). were from liver on S. A for of and Scholar). were from the lipids and in to and with The were for triglyceride and cholesterol the of of for plasma lipid on the the of the liver and the of the were from the mice and in with and were through the liver and were in through the the in the were for in for with lipids and for with for of lipid were from liver and with and face lipid was by the from the mice from the to the the The and the were for a of in and The were and in a that was with lipids for in for and of plaques from the to the including was of plaques of The area of the plaques in a was as a of the total area of the hepatic was to the was as Sinal C.J. regulation of gene expression by bile Biol. Chem. 2005; 280: Scholar) with the was reverse with to the The was by a in a total of with are as necrosis and number and number and and number were for and were as a of for by of for for and for were from to the of the to the of a The were on a and by to that a the was were by the of gene expression data and the 2001; Scholar) a of for were diet with was for are as are study the that of FXR has on atherosclerotic FXR−/− mice were crossed with ApoE−/− mice to generate FXR−/−ApoE−/− with the ApoE−/− mice the FXR−/− mouse model C.J. M. M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Scholar) was to a these mice or the diet increased levels of and cholesterol for a total of acid is in atherogenic to the of lipids and to the inflammatory have that acid is to FXR−/− mice C.J. M. M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; this from atherogenic of the of mice the weight and survival were were in with the of FXR−/−ApoE−/− mice in the were of weight ApoE−/− mice on the diet FXR−/− ApoE−/− mice on a diet to gain weight to a as wild-type, and FXR−/− mice on the FXR−/−ApoE−/− mice on the diet weight FXR−/− and ApoE−/− mice and wild-type mice on the diet The reduced weight gain exhibited by FXR−/−ApoE−/− mice was not to reduced the of this did not from that of wild-type or FXR−/− mice ApoE−/− mice a diet had the highest more the on the of the of mice on and the diet were with the of the FXR−/−ApoE−/− mice on the exhibited survival survival and increased plasma lipids in FXR−/−ApoE−/− apolipoprotein FXR−/−, farnesoid X are as were by diet in a new apolipoprotein FXR−/−, farnesoid X are as were by diet on blood cholesterol levels of ApoE−/− and FXR−/−ApoE−/− mice were of wild-type or FXR−/− mice the diet but did not from FXR−/−ApoE−/− mice by a diet had cholesterol levels on the with blood and of wild-type, FXR−/−, and ApoE−/− respectively on triglyceride levels in FXR−/− and ApoE−/− mice were of wild-type mice on the FXR−/−ApoE−/− triglyceride levels of the on the with blood and in wild-type, FXR−/−, and ApoE−/− respectively on a blood levels of in FXR−/− and FXR−/−ApoE−/− mice were and in wild-type and ApoE−/− levels for FXR−/−ApoE−/− mice were compared with in wild-type and ApoE−/− mice the diet FXR−/−ApoE−/− mice also had plasma levels compared with FXR−/− mice. to a of plasma levels in of the to the the plasma levels were of FXR−/− and FXR−/−ApoE−/− mice. levels did not of the study of in blood lipids by the of FXR in the ApoE−/− mouse involved of the lipoprotein of these mice by of and to the LDL, and were characterized by for apolipoprotein either or the FXR−/− mice had increased and LDL lipids as well as reduced and compared with The HDL was the of in the FXR−/− mice In the ApoE−/− FXR increased the levels of and decreased of HDL apoA-I and This was by with increased associated with and LDL as well as decreased apoA-I and associated with HDL in of the lipoprotein for cholesterol in the plasma of FXR−/−ApoE−/− and ApoE−/− mice revealed that FXR−/−ApoE−/− mice had the highest of cholesterol in the of FXR−/−ApoE−/− and ApoE−/− mice increased plasma cholesterol in the of in The levels of and LDL cholesterol were highest in FXR−/−ApoE−/− mice compared with the In FXR−/−ApoE−/− had increased triglyceride levels compared with ApoE−/− on plasma in the were in FXR−/−ApoE−/− mice on and the diet Given the of the liver in lipid homeostasis and liver for in in to levels of triglyceride and cholesterol and were of liver from mice revealed that FXR−/− and FXR−/−ApoE−/− mice had of focal as by of activated M. during In 2003; 17: Scholar). of necrosis were not in the from wild-type and ApoE−/− mice. A approach to the hepatic of lipid was by of liver with lipids Livers from FXR−/− and FXR−/− ApoE−/− mice have increased lipid on a diet compared with wild-type and ApoE−/− mice on the diet as in liver were from liver and for cholesterol and of FXR−/− and FXR−/−ApoE−/− mice to in hepatic cholesterol mice of the compared with and in wild-type and ApoE−/− respectively on a FXR−/− and FXR−/− ApoE−/− mice had increased hepatic of with of wild-type and ApoE−/− mice increased hepatic in FXR−/− mice FXR−/−ApoE−/− mice and wild-type mice compared with the FXR−/− and FXR−/−ApoE−/− mice the diet had increased levels of hepatic compared with wild-type and ApoE−/− on the triglyceride in the FXR−/− mice were and of wild-type and ApoE−/− on the respectively In with the increased hepatic lipid accumulation, the liver a of were increased for FXR−/− and FXR−/−ApoE−/− mice and compared with wild-type and ApoE−/− mice the In to and lipid of from these expression of the genes for and of was FXR−/−, and FXR−/−ApoE−/− mice had to levels of expression compared with wild-type mice the diet increased levels in FXR−/− and ApoE−/− mice to wild-type mice. FXR−/− ApoE−/− mice exhibited a in gene expression to wild-type to the expression FXR−/− and ApoE−/− mice had expression wild-type of hepatic FXR−/−ApoE−/− mice had expression wild-type mice on the to in levels to wild-type in FXR−/− and ApoE−/− mice. to levels a in FXR−/−ApoE−/− mice in the of atherosclerosis was as well as en face of for lipid-filled from on and the diet of en face and from the mice revealed that wild-type FXR−/− had plaques on this diet FXR−/− ApoE−/− and ApoE−/− mice had of plaques in and en face The of atherosclerosis in from these and ApoE−/− as by of en face was not Challenging wild-type and FXR−/− mice with a diet did not in atherosclerotic as by or en face from these mice In of ApoE−/− and FXR−/− ApoE−/− mice resulted in in the of atherosclerosis in of these mice of atherosclerosis in en face from these mice revealed that the FXR−/−ApoE−/− mice had approximately double the of plaques compared with the ApoE−/− mice to of aortic atherosclerosis in and mice. of atherosclerotic plaques in mice total en face of atherosclerotic plaques in mice total en face compared with ApoE−/− mice on the diet This study the pathological consequences of FXR function for the development of atherosclerotic disease. Challenging mice that FXR and genes with a diet to a to gain weight to a and decreased survival compared with wild-type, FXR−/−, and ApoE−/− mice the of FXR also to of total blood cholesterol and triglyceride levels as well as increased and LDL in the ApoE−/− FXR−/−ApoE−/− mice the on hepatic as by lipid accumulation, focal and increased inflammatory gene expression and plasma of these were associated with the most of atherosclerotic lesion formation and the in the FXR−/−ApoE−/− mice compared with the decreased hepatic expression of the receptor in FXR−/− mice. This was associated with decreased hepatic of HDL cholesterol as well as increased synthesis of atherogenic G. G. Gonzalez F.J. Sinal C.J. The farnesoid is an of cholesterol Biol. Chem. 2003; Scholar). FXR−/− mice of cholesterol G. G. Gonzalez F.J. Sinal C.J. The farnesoid is an of cholesterol Biol. Chem. 2003; Scholar) and from the of these factors are to to the plasma total lipid and lipoprotein exhibited by FXR−/− mice. is for hepatic LDL of of in the liver S. expression is for lipoprotein in the of the low density lipoprotein Clin. Invest. and with K.S. E. in the a of Biol. 2004; Scholar, and Opin. 2000; an of HDL in the plasma of ApoE−/− mice. the atherogenic plasma lipid and lipoprotein exhibited by FXR−/−ApoE−/− when with a the interaction the loss of function of the FXR and of from mice revealed that FXR−/− and FXR−/−ApoE−/− mice had of focal necrosis that were from the of ApoE−/− and wild-type mice the Consistent with this FXR−/− and FXR−/− ApoE−/− mice also exhibited the highest levels of plasma have resulted from the of this from lipid is a of the of liver such as K. The of and liver a model including the role of lipid and hepatic in the to Liver 2004; Scholar). the hepatic of lipid in FXR−/− and FXR−/−ApoE−/− is not that chronic to the of these FXR−/− mice with a characterized by increased plasma bile acids C.J. M. M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Scholar). This have also to the hepatic necrosis in FXR−/− and FXR−/−ApoE−/− mice when a of an inflammatory state in the liver in expression of the receptor and the inflammatory also known as and receptor is on and and is involved in many including activation and of these M.A. and function of the Scholar). is a by macrophages and a of and to and A. necrosis an 2004; Scholar). has also been to induce the of in R. A. Smith H. and necrosis to and systemic activation during in Biol. Scholar). the of and levels in the of FXR−/−ApoE−/− mice most the of expression of these genes in and of the such as macrophages and In increased levels in the FXR−/−ApoE−/− mice have to the of expression in these with the to gain as weight and reduced survival compared with the these data that hepatic and in the HF/HC-challenged FXR−/−ApoE−/− mice. loss of FXR function was not to cause atherosclerosis when mice were with a the of FXR with that of resulted in a of the disease. mice transport the of plasma lipids in HDL and this is to to the of this to atherosclerotic disease. with wild-type FXR−/− mice a plasma lipoprotein characterized by the of increased of atherogenic and LDL in the was that atherosclerosis was in the FXR−/− mice the is in by the liver, is a of LDL, and functions as a for receptors that and from the blood K.S. E. in the a of Biol. 2004; Scholar). is also by and macrophages and is to cholesterol efflux and inflammatory in atherosclerotic and Opin. 2000; Scholar). the increased of ApoE−/− mice to and atherosclerotic from a loss of critical functions in the liver and In although FXR has regulatory roles in hepatic function, the expression of this receptor in macrophages is A. of nuclear receptors and during the of into Biol. 2003; Scholar). despite the plasma lipid of FXR−/− is that macrophages in the walls of these mice to lipid and plaque when the loss of FXR was with the loss of was a interaction in more hepatic function, and atherosclerosis treatment with the selective FXR was to the development of in a mouse model of the disease A. Mangelsdorf D.J. of cholesterol disease by FXR agonists in a mouse 2004; Scholar). this study that modulation of FXR be to a specific disease process and more the therapeutic of this the of FXR function as a novel therapeutic approach for atherosclerosis are not activation of FXR in would lead to decreased conversion of cholesterol to bile an to the treatment of disease and data in study as well as with FXR−/− mice have that the role of FXR in lipid homeostasis is more For FXR−/− mice increased of cholesterol and decreased hepatic of and increased synthesis of G. G. Gonzalez F.J. Sinal C.J. The farnesoid is an of cholesterol Biol. Chem. 2003; Scholar). of these associated with the loss of FXR function that of this receptor would lead to an of systemic lipid homeostasis that be to the treatment of atherosclerosis. In is not known modulation of hepatic FXR function can the inflammatory state the of the wall in to that in the liver in this of the mechanism of an revealed of FXR and a of hepatic cholesterol J. C. J. S. The guggulsterone as an antagonist of the bile acid Endocrinol. 2002; Scholar, P. Y. Gonzalez F.J. Mangelsdorf D.J. Moore D.D. A that cholesterol as an antagonist for 2002; Scholar) as well as and increased hepatic LDL V. S. R. of low density lipoprotein receptor in liver of guggulsterone Scholar). lead to the of of FXR by guggulsterone is but of the FXR gene to and increased atherosclerosis when with loss of to this be by that guggulsterone a number of nuclear receptors and with to that exhibited for FXR T.P. C. et guggulsterone is a receptor Pharmacol. 2005; Scholar). guggulsterone is also a of a number of nuclear receptors, including the and X receptors B. B. activates nuclear receptors and induces gene expression through the X Pharmacol. 2004; Scholar). the in of guggulsterone are to be by of In conclusion, this study that loss of FXR function increased atherosclerosis in the ApoE−/− mouse model of this disease. by the loss of FXR in this model decreased weight gain and survival, increased hepatic and plasma increased hepatic and a more plasma lipoprotein profile. This study is the to a role for FXR in atherosclerosis an in model of the disease. In to nuclear receptors with roles in lipid homeostasis liver X receptors, peroxisome proliferator-activated the of atherosclerosis by of FXR to be a of the loss of function of this receptor in liver and data the pathological consequences of a of FXR function and the for of of the gene for this nuclear receptor with gene known to the risk for cardiovascular disease. The and for for this study was by the of Health is the of a from the Health

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