Effects of FXR in foam-cell formation and atherosclerosis development

Biochim Biophys Acta. 2006 Dec;1761(12):1401-9. doi: 10.1016/j.bbalip.2006.09.018. Epub 2006 Oct 14.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / etiology*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Biological Transport, Active
  • Cholesterol, LDL / metabolism
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Foam Cells / metabolism*
  • Foam Cells / pathology*
  • Gene Expression
  • Homeostasis
  • In Vitro Techniques
  • Lipids / blood
  • Lipoproteins, LDL / metabolism
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Apolipoproteins E
  • Cholesterol, LDL
  • Cytokines
  • DNA-Binding Proteins
  • Lipids
  • Lipoproteins, LDL
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • oxidized low density lipoprotein
  • farnesoid X-activated receptor