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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 張以承 | zh_TW |
| dc.contributor.advisor | Yi-Cheng Chang | en |
| dc.contributor.author | 陳詩宜 | zh_TW |
| dc.contributor.author | Shih-Yi Chen | en |
| dc.date.accessioned | 2021-07-11T15:22:12Z | - |
| dc.date.available | 2024-08-16 | - |
| dc.date.copyright | 2019-03-11 | - |
| dc.date.issued | 2019 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | Reference
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78826 | - |
| dc.description.abstract | PPARγ是一由配體活化的核內受體與轉錄因子。它藉由調控脂肪細胞分化、脂質代謝以及葡萄糖恆定等相關基因的轉錄，影響代謝平衡。Thiazolidinediones (TZDs)是人工合成的PPARγ配體，廣泛使用於治療第二型糖尿病，能夠有效改善胰島素敏感性，但TZDs有水分滯留、體重增加及骨質疏鬆等的副作用，亟待有新型的活化PPARγ方法出現。
PPARγ的內生性配體迄今尚未有定論。在我們團隊先前的研究發現15-keto prostaglandin E2 (15-keto-PGE2) 極可能為PPARγ的內生性配體。15-keto-PGE2是前列腺素E2 (prostaglandin E2, PGE2) 經由NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH)催化產生的下游產物，而15-keto-PGE2會進一步被前列腺素還原酶 (PTGR2) 還原成13,14-dihydro-15-keto-PGE2。在細胞模式中, 我們發現15-keto-PGE2可活化PPARγ，更進一步發現Ptgr2基因剔除鼠在餵食高脂高糖飼料下，相較於對照組老鼠，胰島素敏感性大幅改善。 在此研究中，我們在餵食高脂高糖飼料的老鼠施打15-keto-PGE2，能夠大幅提升胰島素敏感性與改善葡萄糖耐受性。在細胞模式，我們發現15-keto-PGE2在白色脂肪細胞中能夠促進葡萄糖攝取，伴隨有PPARγ下游基因表現增加，15-keto-PGE2並可與PPARγ 配體結合區結合，增加下游報導基因訊號。分子模擬對接實驗顯示，15-keto-PGE2可與PPARγ以共價鍵結合，與pioglitzaone和PPARγ結合模式不相同，藉由液相層析串聯質譜儀分析，我們發現15-keto-PGE2以共價鍵結合在PPARγ半胱胺酸313的位置，並利用相互免疫共沉澱法驗證此結果，若將PPARγ半胱胺酸313突變，則會大幅影響15-keto-PGE2結合PPARγ能力，並消除15-keto-PGE2促進白色脂肪細胞葡萄糖攝取之效果。 這些實驗顯示PPARγ可能的內生性配體15-keto-PGE2會與PPARγ半胱胺酸313形成共價鍵結合，造成PPARγ活化，進而在小鼠與細胞模式中，達到改善胰島素敏感性。 | zh_TW |
| dc.description.abstract | Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor and transcription factor with an essential role in metabolic homeostasis through regulating the transcription of genes involved in adipogenesis, lipid metabolism and glucose homeostasis. The synthetic PPARγ agonists, thiazolidinediones (TZDs), are widely used as anti-diabetic drug owing to their insulin-sensitizing ability. However, TZDs have several side effects, including fluid retention, weight gain and osteoporosis.
The endogenous ligand of PPARγ remains inconclusive. We previously found 15-keto prostaglandin E2 (15-keto-PGE2), a metabolite of prostaglandin E2, was probably an endogenous ligand of PPARγ. Prostaglandin E2 is metabolized to 15-keto-PGE2 by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-keto-PGE2 is further catalyzed to 13, 14-dihydro-15-keto-PGE2 by prostaglandin reductase-2 (PTGR2). In cultured cells, we found that inhibition of PTGR2 increases 15-keto-PGE2, leading to activation of PPARγ. We further found that Ptgr2 knockout mice are more insulin sensitive than wild-type littermates fed on high-fat high-sucrose diet (HFHSD). In this study, 15-keto-PGE2-treatment significantly improved insulin sensitivity and glucose tolerance in mice on HFHSD. We found that 15-keto-PGE2 promoted glucose uptake in white adipocytes, accompanied by upregulation of PPARγ target genes. Molecular docking showed that 15-keto-PGE2 can bind to PPARγ through covalent binding, which is different from the binding of pioglitazone to PPARγ. Liquid chromatography-tandem mass spectrometry analysis data indicated that 15-keto-PGE2 formed a covalent bond with the cysteine-313 residue of PPARγ, which was further confirmed by reciprocal co-immunoprecipitation. The PPARγ-transactivating activity of 15-keto-PGE2 was abolished in cells expressing PPARγ with a cysteine-313 mutation, and enhancement of glucose uptake induced by 15-keto-PGE2 was eliminated. Taken together, these results suggest that 15-keto-PGE2, a potential endogenous ligand of PPARγ, activates PPARγ through covalently binding to Cys313 residue, leading to enhanced insulin sensitivity in both cultured cell and mouse model. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:22:12Z (GMT). No. of bitstreams: 1 ntu-108-R05455005-1.pdf: 2975732 bytes, checksum: 5ee18b9fffdca41e378f2e02cd5f5a2e (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書
謝辭 i 中文摘要 ii 英文摘要 iv Chapter I – Background and Experimental Rational. 1 1. PPARγ is a key transcriptional regulator of metabolism 1 2. The synthetic PPARγ agonists, thiazolidinediones 3 3. 15-keto-PGE2 is an endogenous PPARγ ligand 4 4. Metabolic phenotype of Ptgr2 knockout mice 6 5. Specific aim of this study 7 Chapter II – Materials and Methods. 8 1. Animal model 8 2. Glucose and insulin tolerance test 8 3. In vivo measurement of insulin signaling 9 4. Cell culture 9 5. Plasmid construction and site-directed mutagenesis 10 6. Reporter assay 11 7. RNA extraction, cDNA synthesis and RT-qPCR 11 8. Glucose uptake assay 12 9. Immunoprecipitation and proteomic analysis 13 10. Generation of PPARγ-null 3T3-L1 stable cell lines using CRISPR/Cas9 System 15 11. Lentivirus production and transduction 16 Chapter III – Results. 17 1. The therapeutic effect of 15-keto-PGE2 on glucose intolerance 17 (1) Metabolic phenotype of mice treated with 15-keto-PGE2 17 (2) Effect of 15-keto-PGE2 on insulin signaling 18 2. The metabolic changes induced by 15-keto-PGE2 in white adipocyte 18 (1) Glucose uptake assay in 3T3-L1 adipocytes 18 (2) Effect of 15-keto-PGE2 on expression of Glut4 and PPARγ-downstream genes 19 3. The molecular mechanism by which 15-keto-PGE2 increase glucose uptake 20 (1) 15-keto-PGE2 activates PPARγ-mediated transcription 20 (2) Structure of PPARγ with 15-keto-PGE2 predicted by molecular docking 21 (3) 15-keto-PGE2 is bound to murine PPARγ covalently at Cys313 21 (4) Cys313 is essential for activation of PPARγ by 15-keto-PGE2 22 Chapter IV – Discussion. 24 Figures 27 Tables 41 References 43 | - |
| dc.language.iso | en | - |
| dc.title | 15-keto-PGE2 對胰島素阻抗性之治療作用及其機轉 | zh_TW |
| dc.title | Therapeutic Effect of 15-keto-PGE2 on Insulin Resistance: Molecular Mechanism | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 107-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 莊立民;陳佑宗 | zh_TW |
| dc.contributor.oralexamcommittee | Lee-Ming Chuang;You-Tzung Chen | en |
| dc.subject.keyword | PPARγ,第二型糖尿病,15-keto-PGE2,胰島素敏感性,葡萄糖攝取, | zh_TW |
| dc.subject.keyword | PPARγ,type 2 diabetes,15-keto-PGE2,insulin sensitivity,glucose uptake, | en |
| dc.relation.page | 50 | - |
| dc.identifier.doi | 10.6342/NTU201701626 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2019-02-12 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | - |
| dc.date.embargo-lift | 2024-03-11 | - |
| Appears in Collections: | 基因體暨蛋白體醫學研究所 | |
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