BACKGROUND/
AIMS:
Both the farnesoid X receptor (FXR) and
peroxisome proliferator-activated receptor (
PPAR)
play important
roles in
lipid metabolism and
atherosclerosis. We investigated the interaction between FXR and
PPARgamma.
METHODS:
Apolipoprotein E knockout (
ApoE-/-)
mice and FXR knockout (FXR-/-)
mice were crossed to generate
ApoE-/-FXR-/-
mice. The
mice were divided into
ApoE-/-,
ApoE-/-FXR-/-, and
ApoE-/-FXR-/- +
pioglitazone groups. All
mice were fed a high-fat, high-
cholesterol diet for 12 weeks. The
ApoE-/-FXR-/- +
pioglitazone group was also treated with
pioglitazone, 20 mg/kg
body weight.
Body weight,
blood glucose level,
lipid profile, and
liver enzyme levels were measured. To evaluate atherosclerotic lesions, the
aorta was stained with Oil red O.
RESULTS:
There were no differences in
body weight or
blood glucose level among the three groups. The
serum lipid concentration and
liver enzyme levels increased in the
ApoE-/-FXR-/- group compared with the
ApoE-/- group (p < 0.01). The
ApoE-/-FXR-/- +
pioglitazone group had lower
high-density lipoprotein (HDL) (55 +/- 4 vs. 28 +/- 2 mg/dL, p < 0.01) and
low-density lipoprotein (LDL) (797 +/- 26 vs. 682 +/- 47 mg/dL, p = 0.04)
cholesterol than the
ApoE-/-FXR-/- group. The respective percentages of aortic
atherosclerotic plaques in the
ApoE-/-,
ApoE-/-FXR-/-, and
ApoE-/-FXR-/- +
pioglitazone groups were 2.7 +/- 0.2%, 7.7 +/- 1.2%, and 18.6 +/- 1.0%. In
ApoE-/-FXR-/-
mice, the
administration of
pioglitazone significantly increased the number of atherosclerotic lesions (p = 0.02).
CONCLUSIONS:
Pioglitazone increased the number of
atherosclerotic plaques in
ApoE-/-FXR-/-
mice. This suggests that when FXR is inhibited, the activation of
PPARgamma can aggravate
atherosclerosis.