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Influence of Constitutive Androstane Receptor Activity on the Effects of Pioglitazone on Non-alcoholic Fatty Liver Disease
Constitutive Androstane Receptor의 활성도가 Pioglitazone에 의한 비알콜성지방간 변화에 미치는 영향

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Authors
안화영
Advisor
박영주
Major
의과대학 의학과
Issue Date
2014-02
Publisher
서울대학교 대학원
Keywords
non-alcoholic fatty liver diseasethiazolidinedionedrug metabolismPPARγ
Description
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 박영주.
Abstract
INTRODUCTION: We examined whether the effects of pioglitazone on metabolic parameters are different according to the activities of constitutive androstane receptor (CAR) in diet induced obesity mice. Also, we investigated the interaction between pioglitazone/peroxisome proliferator-activated receptor γ (PPAR γ) and CAR.
RESEARCH DESIGN AND METHODS: Three mg/kg of TCPOBOP were injected weekly for CAR activation, and CAR-/- mice were used for CAR depletion. Mice with different CAR activities were subsequently divided into two groups for pioglitazone treatment. To make a diet induced obesity model, high fat diet was supplied to the high fat diet group. We checked body weight changes every week. After 12 weeks, glucose tolerance test was performed and the serum levels of cholesterol and pioglitazone and liver histology were examined. Fatty acid oxidation rate was measured using [14C]palmitate. Gene expressions related to lipid metabolism were analyzed using real time PCR.
RESULTS: Pioglitazone-treated CAR-/- mice showed less weight gain, comparable improvement of glucose tolerance, and significant improvement of non-alcoholic fatty liver disease (NAFLD) compared with untreated mice. In TCPOBOP treated mice, there was no significant difference by pioglitazone treatment due to the strong effect of TCPOBOP. We identified that activation of CAR by high concentration of pioglitazone was not related to the improvement of NAFLD in CAR-/- mice. Among genes related to lipid metabolism, the expressions of CD36 and SCD-1 were decreased in pioglitazone-treated CAR-/- mice compared with those of pioglitazone-treated CAR+/+ mice. These changes might have been regulated by decreased PPARγ2 expression.
CONCLUSIONS: The metabolism of pioglitazone affected by CAR activity was independent of the serum pioglitazone concentration. Decreased PPARγ2 expression by pioglitazone in CAR deleted state might play a role to improve NAFLD possibly through regulating the expressions of CD36 and SCD-1 transiently.
Language
English
URI
https://hdl.handle.net/10371/121973
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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