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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
DC Field | Value | Language |
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dc.contributor.advisor | 박영주 | - |
dc.contributor.author | 안화영 | - |
dc.date.accessioned | 2017-07-14T01:27:04Z | - |
dc.date.available | 2017-07-14T01:27:04Z | - |
dc.date.issued | 2014-02 | - |
dc.identifier.other | 000000016942 | - |
dc.identifier.uri | https://hdl.handle.net/10371/121973 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 박영주. | - |
dc.description.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. | - |
dc.description.tableofcontents | ABSTRACT i
CONTENTS iii LIST OF TABLES AND FIGURESvi LIST OF ABBREVIATIONSviii INTRODUCTION1 1. Metabolic regulation by thiazolidinediones1 2. Various responses of individual patients to the pioglitazone treatment2 3. Metabolism of pioglitazone2 4. Changes of drug metabolism according to CAR activity3 5. Metabolic regulation of CAR5 6. Pathogenesis of non-alcoholic fatty liver disease and the role of CAR and TZDs during steatosis6 7. Possible interaction between CAR and PPAR8 8. Aim of study9 MATERIAL AND METHODS10 1. Animals and study design10 2. Materials12 3. Measurement of body weight and glucose tolerance12 4. Measurement of lipid profile, liver enzyme and insulin13 5. Fatty acid oxidation13 6. Histology14 7. Measurement of pioglitazone concentration14 8. RNA isolation and quantitative real time PCR15 9. Statistical analysis15 RESULTS17 1. Changes of body weight, organ weights and glucose tolerance by pioglitazone treatment in diet induced obesity mice with different CAR activity17 2. Measurements of serum lipids and liver enzymes in CAR+/+ and CAR-/- mice18 3. The improvement of NAFLD in pioglitazone-treated CAR-/- mice22 4. Differences in the expression of Cytochrome P450s and the concentration of serum pioglitazone between CAR-/- and CAR+/+ mice24 5. Concentration-independent improvement of NAFLD in pioglitazone-treated CAR-/- mice25 6. Comparable rates of fatty acid oxidation and expressions of genes related to fatty acid oxidation between pioglitazone-treated CAR+/+ and CAR-/- mice29 7. Different expressions of genes associated with lipid transport between pioglitazone-treated CAR+/+ and CAR-/- mice36 8. Different expressions of genes related to lipogenesis between pioglitazone-treated CAR+/+ and CAR-/- mice39 9. Different expressions of PPARγ and PGC-1α between pioglitazone-treated CAR+/+ and CAR-/- mice43 DISCUSSION48 REFERENCES54 국문초록67 | - |
dc.format | application/pdf | - |
dc.format.extent | 1906936 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | non-alcoholic fatty liver disease | - |
dc.subject | thiazolidinedione | - |
dc.subject | drug metabolism | - |
dc.subject | PPARγ | - |
dc.subject.ddc | 610 | - |
dc.title | Influence of Constitutive Androstane Receptor Activity on the Effects of Pioglitazone on Non-alcoholic Fatty Liver Disease | - |
dc.title.alternative | Constitutive Androstane Receptor의 활성도가 Pioglitazone에 의한 비알콜성지방간 변화에 미치는 영향 | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | viii, 68 | - |
dc.contributor.affiliation | 의과대학 의학과 | - |
dc.date.awarded | 2014-02 | - |
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