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KMID : 0882420130840020238
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Korean Journal of Medicine
2013 Volume.84 No. 2 p.238 ~ p.244
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Effects of FXR Deficiency and Pioglitazone on Atherosclerosis in ApoE-Knockout Mice
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Park Young-Joo
Kim Min-Joo
Lee Kwan-Jae
Hwang Ji-Yeon
Lee Ye-Nna
Ahn Hwa-Young
Choi Sung-Hee
Moon Min-Kyong
Lim Soo
Jang Hak-Chul
Yi Ka-Hee
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Abstract
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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 PPARγ.
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 PPARγ can aggravate atherosclerosis.
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KEYWORD
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Farnesoid X-activated receptor, Peroxisome proliferator-activated receptors, Pioglitazone, Atherosclerosis
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