Effects of FXR in foam-cell formation and atherosclerosis development.
Farnesoid X receptor (FXR), a bile-acid-activated member of the nuclear receptor superfamily, is essential in regulating bile-acid, cholesterol, and triglyceride homeostasis. Disruption of the FXR gene in mice results in a proatherosclerotic lipid profile with increased serum cholesterols and triglycerides. However, the role of FXR in foam-cell formation and atherosclerosis development remains unclear. The current study showed that the peritoneal macrophages isolated from FXR-null mice took up less oxidized LDL-cholesterol (oxLDL-C), which was accompanied by a marked reduction in CD36 expression in these cells. This result appears to be FXR-independent, as FXR was not detected in the peritoneal macrophages. To assess to what extent FXR modulates atherosclerosis development, FXR/ApoE double-null mice were generated. Female mice were used for atherosclerosis analysis. Compared to ApoE-null mice, the FXR/ApoE double-null mice were found to have less atherosclerotic lesion area in the aorta, despite a further increase in the serum cholesterols and triglycerides. Our results indicate that disruption of the FXR gene could attenuate atherosclerosis development, most likely resulting from reduced oxLDL-C uptake by macrophages. Our study cautions the use of serum lipid levels as a surrogate marker to determine the efficiency of FXR modulators in treating hyperlipidemia.
Guo
Grace L
GL
Laboratory of Metabolism, Bldg. 37, Rm. 3106B, NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Santamarina-Fojo
Silvia
S
Akiyama
Taro E
TE
Amar
Marcelo J A
MJ
Paigen
Beverly J
BJ
Brewer
Bryan
B
Gonzalez
Frank J
FJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001693:Biological Transport, Active; D008078:Cholesterol, LDL / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression; D006706:Homeostasis; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D016207:Cytokines; D004268:DNA-Binding Proteins; D008055:Lipids; D008077:Lipoproteins, LDL; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099252:oxidized low density lipoprotein