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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
dc.contributor.advisor백성희-
dc.contributor.author김경규-
dc.date.accessioned2017-10-27T17:13:08Z-
dc.date.available2017-10-27T17:13:08Z-
dc.date.issued2017-08-
dc.identifier.other000000145581-
dc.identifier.urihttps://hdl.handle.net/10371/137155-
dc.description학위논문 (박사)-- 서울대학교 대학원 자연과학대학 생명과학부, 2017. 8. 백성희.-
dc.description.abstractHepatic 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.tableofcontentsABSTRACT 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
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dc.formatapplication/pdf-
dc.format.extent5893983 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectRetinoic acid receptor-related orphan receptor a (RORa)-
dc.subjectLiver-specific Rora deficient mice-
dc.subjectHigh fat diet-
dc.subjectObesity-
dc.subjectLiver-
dc.subjectLipid metabolism-
dc.subjectPeroxisome proliferators-activated receptor g (PPARg)-
dc.subjectGW9662-
dc.subjectHistone deacetylase 3 (HDAC3)-
dc.subject.ddc570-
dc.title간에서의 RORa에 의한 지방 항상성 유지 조절 기작에 관한 연구-
dc.title.alternativeStudies on the Regulatory Mechanism of Hepatic Lipid Homeostasis by RORa-
dc.typeThesis-
dc.contributor.AlternativeAuthorKyeongkyu Kim-
dc.description.degreeDoctor-
dc.contributor.affiliation자연과학대학 생명과학부-
dc.date.awarded2017-08-
Appears in Collections:
College of Natural Sciences (자연과학대학)Dept. of Biological Sciences (생명과학부)Theses (Ph.D. / Sc.D._생명과학부)
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