The Korean Journal of Medicine

The Korean Association of Internal Medicine (대한내과학회)
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Effects of FXR Deficiency and Pioglitazone on Atherosclerosis in ApoE-Knockout Mice

ApoE 결손 생쥐에서 FXR 결핍과 피오글리타존이 동맥경화에 미치는 영향

  • Park, Young Joo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Kim, Min Joo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Lee, Kwan Jae (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Hwang, Ji-Yeon (Preclinical Research Center, Biomedical Research Institute, Seoul National University Bundang Hospital) ;
  • Lee, Yenna (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Ahn, Hwa Young (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Choi, Sung Hee (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Moon, Min Kyong (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Lim, Soo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Jang, Hak C. (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Yi, Ka Hee (Department of Internal Medicine, Seoul National University College of Medicine)
  • 박영주 (서울대학교 의과대학 내과학교실) ;
  • 김민주 (서울대학교 의과대학 내과학교실) ;
  • 이관재 (분당서울대학교병원 내과) ;
  • 황지연 (분당서울대학교병원 의생명연구원 전임상실험센터) ;
  • 이예나 (서울대학교 의과대학 내과학교실) ;
  • 안화영 (서울대학교 의과대학 내과학교실) ;
  • 최성희 (서울대학교 의과대학 내과학교실) ;
  • 문민경 (서울대학교 의과대학 내과학교실) ;
  • 임수 (서울대학교 의과대학 내과학교실) ;
  • 장학철 (서울대학교 의과대학 내과학교실) ;
  • 이가희 (서울대학교 의과대학 내과학교실)
  • Received : 2013.01.03
  • Accepted : 2013.01.08
  • Published : 2013.02.01
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Abstract

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 $PPAR{\gamma}$. 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 ${\pm}$ 4 vs. 28 ${\pm}$ 2 mg/dL, p < 0.01) and low-density lipoprotein (LDL) (797 ${\pm}$ 26 vs. 682 ${\pm}$ 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 ${\pm}$ 0.2%, 7.7 ${\pm}$ 1.2%, and 18.6 ${\pm}$ 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 $PPAR{\gamma}$ can aggravate atherosclerosis.

목적: Farnesoid X receptor (FXR)와 peroxisome proliferator- activated receptor (PPAR)는 둘 다 지질 대사와 동맥경화에 중요한 역할을 담당하고 있어 이들의 상호작용에 대해 알아보고자 하였다. 방법: 아포지질단백질 E가 결손된($ApoE^{-/-}$) 생쥐에 추가로 FXR을 결손시켜 $ApoE^{-/-}FXR^{-/-}$ 생쥐를 만들었다. 생쥐는 $ApoE^{-/-}$군, $ApoE^{-/-}FXR^{-/-}$군, $ApoE^{-/-}FXR^{-/-}$ + pioglitazone군, 3군으로 나누어 12주간 고지방 고콜레스테롤 식이를 먹였고 $ApoE^{-/-}FXR^{-/-}$ + pioglitazone군은 pioglitazone을 하루에 몸무게 kg당 20 mg을 식이에 섞어 투여하였다. 이후 체중, 혈당, 혈청 지질 농도, 간효소치를 측정하였다. 대동맥에서 Oil red O 염색을 통해 동맥경화반을 평가하였다. 결과: 세 군 사이에 체중과 혈당에는 차이가 없었다. $ApoE^{-/-}$ $FXR^{-/-}$군은 $ApoE^{-/-}$군에 비하여 모든 종류의 지질 농도와 간효소치가 유의하게 증가하였다(p < 0.01). $ApoE^{-/-}FXR^{-/-}$ + pioglitazone군은 $ApoE^{-/-}FXR^{-/-}$군에 비하여 HDL 콜레스테롤과(55 ${\pm}$ 4 mg/dL vs. 28 ${\pm}$ 2 mg/dL, p < 0.01) LDL 콜레스테롤이(797 ${\pm}$ 26 mg/dL vs. 682 ${\pm}$ 47 mg/dL, p = 0.04) 유의하게 감소하였다. 동맥경화반은 $ApoE^{-/-}$군, $ApoE^{-/-}FXR^{-/-}$군, $ApoE^{-/-}FXR^{-/-}$ + pioglitazone군에서 각각 2.7 ${\pm}$ 0.2%, 7.7 ${\pm}$ 1.2%, 18.6 ${\pm}$ 1.0%로 증가하였다. $ApoE^{-/-}FXR^{-/-}$ 생쥐에서 pioglitazone의 투여는 유의하게 동맥경화를 증가시켰다(p = 0.02). 결론: 본 연구에서 $ApoE^{-/-}FXR^{-/-}$ 생쥐에서 pioglitazone의 투여는 동맥경화반의 발생을 증가시켜 FXR이 억제된 상태에서 $PPAR{\gamma}$의 활성화는 동맥경화에 나쁜 영향을 미칠 수 있음을 시사하였다.

Keywords

References

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