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간에서의 RORa에 의한 지방 항상성 유지 조절 기작에 관한 연구 : Studies on the Regulatory Mechanism of Hepatic Lipid Homeostasis by RORa
DC Field | Value | Language |
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dc.contributor.advisor | 백성희 | - |
dc.contributor.author | 김경규 | - |
dc.date.accessioned | 2017-10-27T17:13:08Z | - |
dc.date.available | 2017-10-27T17:13:08Z | - |
dc.date.issued | 2017-08 | - |
dc.identifier.other | 000000145581 | - |
dc.identifier.uri | https://hdl.handle.net/10371/137155 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 자연과학대학 생명과학부, 2017. 8. 백성희. | - |
dc.description.abstract | Hepatic metabolic dysregulation has been shown to induce fatty liver, insulin resistance and obesity. The retinoic acid receptor-related orphan receptor a (RORa) is an important regulator of various biological processes, including cerebellum development, circadian rhythm, and cancer. Here, I find that hepatic RORa regulates lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor g (PPARg), a nuclear receptor that mediates hepatic lipid metabolism. Liver-specific Rora deficient mice develop hepatic steatosis, obesity, and insulin resistance, when challenged with a high fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rora leads to the dysregulation of PPARg signaling to increase hepatic glucose and lipid metabolism. RORa specifically binds and recruits HDAC3 to the PPARg target promoters for the transcriptional repression of PPARg activity. Finally, PPARg antagonism remarkably restores metabolic homeostasis in HFD-fed liver-specific Rora deficient mice. Taken together, my data indicate that RORa plays a pivotal role in the regulation of hepatic lipid homeostasis. Therefore, therapeutic strategies designed to modulate RORa activity may be beneficial for the treatment of metabolic disorders, including hepatic steatosis and obesity. | - |
dc.description.tableofcontents | ABSTRACT i
CONTENTS iii LIST OF FIGURES AND TABLES vi CHAPTER I. Introduction 1 I-1. Orphan Nuclear Receptors and RORa 2 1.1. General information of orphan nuclear receptors 2 1.2. Structure of orphan nuclear receptors 2 1.3. General information of RORa 5 1.4. RORa in metabolism 7 I-2. Peroxisome proliferator-activated receptor g (PPARg) 9 2.1. General information of PPARg 9 2.2. PPARg activators, Thiazolidinediones 9 2.3 PPARg in metabolism 11 I-3. Histone deacetylase 3 (HDAC3) 14 3.1. General information of Histone deacetylases 14 3.2. Physiological functions of HDAC3 16 I-4. Metabolic disorder 18 4.1. Obesity 18 4.2. Hepatic steatosis 19 CHAPTER II. Liver-specific Rora deficient mice are susceptible to diet-induced obesity 22 II-1. Summary 23 II-2. Introduction 24 II-3. Results 27 II-4. Discussion 47 II-5. Materials and Methods 49 CHAPTER III. RORa requires HDAC3 to regulate PPARg signaling to maintain hepatic lipid homeostasis in response to over-nutrient cue 56 III-1. Summary 57 III-2. Introduction 58 III-3. Results 61 III-4. Discussion 106 III-5. Materials and Methods 109 CHAPTER IV. Conclusion 115 REFERENCES 123 국문초록 / ABSTRACT IN KOREAN 135 | - |
dc.format | application/pdf | - |
dc.format.extent | 5893983 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Retinoic acid receptor-related orphan receptor a (RORa) | - |
dc.subject | Liver-specific Rora deficient mice | - |
dc.subject | High fat diet | - |
dc.subject | Obesity | - |
dc.subject | Liver | - |
dc.subject | Lipid metabolism | - |
dc.subject | Peroxisome proliferators-activated receptor g (PPARg) | - |
dc.subject | GW9662 | - |
dc.subject | Histone deacetylase 3 (HDAC3) | - |
dc.subject.ddc | 570 | - |
dc.title | 간에서의 RORa에 의한 지방 항상성 유지 조절 기작에 관한 연구 | - |
dc.title.alternative | Studies on the Regulatory Mechanism of Hepatic Lipid Homeostasis by RORa | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Kyeongkyu Kim | - |
dc.description.degree | Doctor | - |
dc.contributor.affiliation | 자연과학대학 생명과학부 | - |
dc.date.awarded | 2017-08 | - |
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