Effects of FXR in foam-cell formation and atherosclerosis development.
Apolipoproteins-E, Atherosclerosis, Biological-Transport-Active, Cholesterol-LDL, Cytokines, DNA-Binding-Proteins, Female, Foam-Cells, Gene-Expression, Homeostasis, Lipids, Lipoproteins-LDL, Macrophages-Peritoneal, Mice, Mice-Inbred-C57BL, Mice-Knockout, Receptors-Cytoplasmic-and-Nuclear, Transcription-Factors
Biochim Biophys Acta 2006 Dec; 1761(12):1401-9.
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, G L.; Santamarina, Fojo S.; Akiyama, T E.; Amar, M J.; Paigen, B J.; Brewer, B; and Gonzalez, F J., "Effects of FXR in foam-cell formation and atherosclerosis development." (2006). Faculty Research 2000 - 2009. 1436.