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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/35616完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂紹俊 | |
| dc.contributor.author | Mei-Ling Chang | en |
| dc.contributor.author | 張美鈴 | zh_TW |
| dc.date.accessioned | 2021-06-13T07:01:18Z | - |
| dc.date.available | 2010-07-30 | |
| dc.date.copyright | 2005-07-30 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-27 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/35616 | - |
| dc.description.abstract | 肥胖引起之胰島素抗性是造成代謝性症候群的主要因子，而adipokines在胰島素抗性扮演重要的角色。Leptin具『抗肥胖荷爾蒙』的角色，參與能量恆定調節，本論文欲探討，攝取高油飲食，餐後之TRL（triacyglycerol-rich lipoproteins）是否影響ob基因表現。由於發炎反應和氧化壓力參與胰島素抗性發生，故探討發
炎誘發劑LPS和氧化壓力來源H2O2對具有抗胰島素特性之resistin的影響及其可能調節機制。 在TRL 對ob 基因影響的實驗中，因為長期攝取高油飲食易造成肥胖，攝食高油飲食後，血液中會出現高濃度的TG（triacylglycerol），TG 主要利用TRL運送至周邊組織，所以探討高油飲食後之TRL 是否影響ob 基因表現。雄性Wistar大鼠經過禁食48 小時後，分別給予高油飼料或無油高醣飼料，復食30 分鐘移走 飼料，分別在復食後第2、4 和8 小時犧牲。結果，高油組大鼠的血漿TG 濃度顯著較高（p < 0.05），血漿中leptin 濃度和脂肪組織之ob mRNA 表現顯著低於無油高醣組（p < 0.05）；兩組之血漿葡萄糖和胰島素濃度沒有顯著差異。高油組血漿TRL 濃度顯著高於無油高醣組，推測TRL 可能參與調節ob mRNA 表現。收集大鼠管餵5mL 大豆油3 小時後之血漿TRL，處理已分化之3T3-L1 脂肪細胞，結果顯示，TRL 顯著抑制3T3-L1 脂肪細胞之ob mRNA 表現，呈現劑量和時間效應，並且可抑制胰島素所提高之ob mRNA 表現。從結果得知，高油飲食餐後有較低ob mRNA 表現和血漿leptin 濃度，可能是因為TRL 抑制ob 基因表現所致。 在囓齒科動物，resistin主要在脂肪組織表現，且參與胰島素抗性之作用。人類resistin mRNA在單核球細胞表現最高，推測resistin在發炎反應和氧化壓力引起之胰島素抗拒扮演重要的角色。於是利用LPS誘發發炎反應，以及H2O2當氧化壓力來源，探討單核球細胞和巨噬細胞在模擬生物體之發炎反應和氧化壓力環境下，其resistin mRNA表現之變化，並探討其可能之調節機制。在LPS引起發炎反 應之實驗，LPS顯著提高RAW264.7 巨噬細胞和小鼠肝臟巨噬細胞resistin mRNA表現。抗發炎試劑dexametasone、genistein和PPARγ 之agonists（ciglitazone、pioglitazone和15d-PGJ2），顯著地抑制經由LPS刺激提高resistin mRNA的作用。從actinomycin D降低LPS刺激所提高之resistin RNA表現量，可知LPS在轉錄層次調控resistin RNA表現。PI3K、ERK1/2 和NF-κB之各別抑制劑Ly293002（25 nM）、U0126（2.5 μM）和CAPE（10 μg/mL）阻斷LPS對resistin mRNA的活化，且免疫螢光染色分析可見NF-κB之p50 subunit大量轉位至細胞核。綜合以上結果，PI3K、ERK和NF-κB參與LPS對巨噬細胞之resistin mRNA的活化作用。 當以H2O2處理，THP-1 和人類PBMC（peripheral blood mononuclear cells）resistin mRNA的表現量明顯增加。由actinomycin D抑制H2O2對resistin mRNA的活化，可知H2O2經由轉錄層次驅動resistin mRNA表現。在THP-1 細胞，NF-κB之抑制劑CAPE（10 μg/mL）顯著地降低H2O2所增加之resistin mRNA含量，且p50 subunit因H2O2處理而大量轉位至細胞核，得知NF-κB參與H2O2以促進resistin mRNA表現。此外，H2O2並不影響TNF-α之表現，因此H2O2提高resistin mRNA表現之機制，有別於LPS的活化作用。 | zh_TW |
| dc.description.abstract | Obesity is the most common cause of metabolic syndrome. Adipocytes produce a variety of biologically active molecules, collectively known as adipokines,including leptin, resistin, TNF-α and adiponectin. These adipokines participates in the metablic syndrome. Leptin acts as an satiety factor and anti-obesity hormone, to control appetite and energy expenditure. The present studies, examine the possible role of triacylglycerol-rich lipoproteins in the down-regulation of adipose obese gene
expression in rats re-fed a high-fat diet. Because inflammation and oxidative stress are also believed to be implicated in the pathophysiology of insulin resistance in metabolic diseases, the effect of LPS and H2O2 on resistin mRNA expression was studied in monocytes and macrophages. The large amount of absorbed dietary lipid after feeding a high-fat diet is mainly transported as triacylglycerol (TG)-rich lipoproteins (TRL) in the post-prandial blood and is subsequently distributed to peripheral tissues including adipose and muscle tissues. An in vivo and an in vitro study were conducted to investigate the possible role of post-prandial TRL after high fat feeding in the regulation of obese (ob) gene expression. Adult male Wistar rats were fasted for 48 h and re-fed with either a fat-free/high-carbohydrate diet or a high-fat diet for 2, 4, or 8 h. Rats re-fed the high-fat diet had significantly higher plasma TG (p < 0.05) and lower plasma leptin and adipose ob mRNA (p < 0.05) than those fed the fat-free/high-carbohydrate diet; however, plasma glucose and insulin concentrations were not significantly different between the two groups. Plasma lipid analysis found large amount of TRL in rats fed with the high-fat diet; however, only very small amount of the TRL was found in rats fed with the fat-free/high-carbohydrate diet. We speculated that TRL might be involved in regulation of ob gene expression. To further examine the after of TRL on ob mRNA expression, differentiated 3T3-L1 adipocytes were treated with TRL collected from rats fed 5 mL soybean oil by gastric intubations. TRL down-regulated ob mRNA not only in a dose and time dependent manner but also in the presence of insulin in 3T3-L1 adipocytes. These results suggest a possible role of TRL in the down-regulation of adipose ob mRNA expression and may account, at least in part, for the previous observations that short-term high fat feeding resulted in lower plasma leptin. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain. In human, resistin is mainly expressed in monocytes, it may be involved in insulin resistance which induced by inflammation and oxidative stress. Therefore the effect of LPS and H2O2 on resistin mRNA expression was examined in monocytes and macrophages. LPS led to a significant increase of resistin mRNA in a dose and time dependent manner in RAW264.7 cells and Kuffer’s cells. Induction of resistin mRNA was attenuated by anti-inflammatory reagents, such as dexametasone, genistein and PPARγ agonists (ciglitazone, pioglitazone and 15d-PGJ2), which suggest that resistin is involved in inflammation process. Actinomycin D inhibit the resistin mRNA activation by LPS, indicated that the LPS increased resistin mRNA through the transcriptional activation. LPS-induced increase of resistin mRNA was blocked by U0126 (2.5 μM) and Ly294002 (25 nM). These results suggest that the MEK and PI3K are involved in the LPS-induced increase of resistin mRNA. NF-κB translocation inhibitor, CAPE (10 μg/mL), inhibited translocation of NF-κB to nucleus and blocked LPS-induced increase of resistin mRNA. These results suggest that NF-κB activation is necessary for resistin induction by LPS. Resistin mRNA expression was induced by H2O2 treatment in THP-1 cells and human’s PBMC. Induction of resistin was also attenuated by transcriptional inhibitor drugs, actinomycin D. Treatment of the cells with NF-κB inhibitor, CAPE (10 μg/mL), prevented increase of resistin mRNA upon H2O2 treatment. The p50 subunit was translocated to nucleus after H2O2 administration. These results suggest that the NF-κB is involved in the H2O2-induced increase of resistin mRNA expression. TNF-α is not involved in H2O2 induction of resistin mRNA, but involved in LPS induction process. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T07:01:18Z (GMT). No. of bitstreams: 1 ntu-94-D86623704-1.pdf: 3906814 bytes, checksum: d90589b10d09ba940bf72464e804026a (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 目錄
第一章緒言與研究目的1 第二章文獻回顧3 第一節Adipokines 簡介3 壹、脂肪組織是一內分泌器官3 貳、Adipokines定義4 參、Adipokines 在胰島素作用扮演的角色5 一、增加胰島素敏感度的adipokines：leptin 和adiponectin 5 二、造成胰島素抗性的adipokines：resistin、TNF-α、IL-6 和ASP 7 三、與心血管疾病有關的adipokines：angiotensinogen 和PAI-1 8 第二節Leptin 簡介10 壹、Leptin 發現起源10 貳、Ob 基因10 參、Leptin 受體（Leptin receptors，Ob-R） 11 肆、Leptin 運輸和作用12 伍、Leptin 生理功能13 陸、Leptin 在中樞神經系統扮演的角色13 柒、Leptin 在周邊組織扮演的角色15 捌、其它作用15 玖、Leptin 在能量恆定扮演的角色16 一、Leptin 是一抗肥胖荷爾蒙（anti-obesity hormone） 16 二、Leptin 是一饑餓訊息（starvation signal） 17 拾、Leptin 表現的調解18 一、脂肪細胞大小18 二、禁食-攝食18 三、內分泌素18 四、葡萄糖和脂質19 五、發炎物質19 六、其它因素的影響19 第三節Resistin 簡介20 壹、Resistin 的發現20 貳、Resistin 結構與生化特性22 參、Resistin 表現的調控24 一、胰島素感受性藥物24 二、身體脂質含量、存在位置26 三、胰島素和葡萄糖的調控27 四、糖皮質固醇和甲狀腺腺素的調控27 五、發炎反應28 六、其它因素的影響29 肆、Resistin生理作用29 一、血糖恆定、抗胰島素作用29 二、Adipogenesis 31 三、心血管疾病、發炎反應31 四、在中樞神經系統扮演的角色32 伍、Resistin在小鼠與人類之差異32 陸、人類resistin的研究33 一、基因學、基因多型性分析33 二、組織特異性34 三、胰島素抗性35 柒、發炎反應與胰島素抗性的關係35 一、Innate immunity 簡介35 二、肥胖、脂肪組織和發炎反應的關係37 捌、氧化壓力與胰島素抗性的關係41 一、氧化壓力41 二、氧化壓力與胰島素抗性的關係41 第三章富含三酸甘油酯脂蛋白對ob 基因表現之影響43 第一節動機與假說43 第二節材料與方法45 壹、動物實驗45 一、實驗一：無油高醣和高油飼料對大鼠脂肪組織leptin mRNA 表 現的影響45 二、實驗二：富含三酸甘油酯脂蛋白之分離45 貳、細胞實驗：3T3-L1 細胞培養45 參、血漿生化學分析46 一、葡萄糖分析46 二、三酸甘油酯分析46 三、胰島素濃度分析47 四、Leptin 濃度分析47 五、Lipoprotein 膠體電泳48 肆、Leptin mRNA 測定48 一、脂肪組織total RNA 抽取48 二、細胞RNA 抽取49 三、Northern blot assay 49 第三節結果52 壹、攝食狀況52 貳、血漿葡萄糖、胰島素、瘦素（leptin）和三酸甘油脂（TG）濃度52 參、無油高醣和高油飲食對大鼠脂肪組織ob mRNA 表現之影響52 肆、無油高醣和高油飲食影響對大鼠血漿脂蛋白組成52 伍、TRL 抑制3T3-L1 脂肪細胞ob mRNA 的表現53 陸、TRL 抑制胰島素對ob mRNA 的活化53 第四節討論54 壹、高油飲食攝食後飯後血漿TRL 參與調控ob 基因的表現54 貳、高油飲食在長、短期對血漿leptin 濃度的影響55 參、分化方法之差異不影響TRL 對ob mRNA 的抑制作用55 第五節結論56 第四章LPS 對巨噬細胞和單核球細胞resistin mRNA 表現的影響57 第一節動機與假說57 第二節材料與方法58 壹、細胞實驗58 一、RAW264.7 細胞58 二、Kupffer 細胞58 三、THP-1 細胞58 四、人類周邊血液單核球細胞59 貳、Resistin mRNA 測定59 一、細胞total RNA 抽取59 二、RT-PCR 60 三、Southern blot assay 60 參、免疫螢光染色（Immunofluorescent stain） 61 第三節結果63 壹、分析方法建立63 貳、LPS 對RAW264.7 巨噬細胞和小鼠肝臟巨噬細胞resistin mRNA 表 現之影響63 一、RAW264.7 巨噬細胞63 二、小鼠肝臟巨噬細胞（kupffer cell） 63 參、LPS 在轉錄層次調控巨噬細胞resistin mRNA 的表現64 肆、自由基（free radical）是否參與LPS 對resistin mRNA 的活化64 伍、抗發炎藥物對LPS 活化resistin mRNA 表現之影響64 一、類固醇類藥物：dexamethasone 拮抗LPS 對resistin mRNA 活 化65 二、Genistein 抑制LPS 的活化作用65 三、PPAR-γ agonist：ciglitazone、pioglitazone和15d-PGJ2拮抗LPS 對resistin mRNA活化65 陸、LPS 經由什麼路徑活化resistin mRNA 表現？ 66 一、JNK 抑制劑：SP600125 對LPS 活化resistin mRNA 表現的影 響66 二、p38 kinase 抑制劑：SB203580 對LPS 誘發resistin mRNA 表現 的影響66 三、PKC 抑制劑：Ro318220 對LPS 活化resistin mRNA 表現的影 響66 四、ERK 抑制劑：U0126 抑制LPS 對resistin mRNA 的活化67 五、PI3K/Akt 抑制劑：Ly294002 拮抗LPS 對resistin mRNA 的活 化67 六、NF-κB抑制劑：CAPE抑制LPS對RAW264.7 細胞resistin mRNA 表現68 第四節討論69 壹、Resistin 在發炎反應扮演重要的角色69 一、LPS 誘發巨噬細胞resistin mRNA 表現69 二、抗發炎藥物拮抗LPS 對resistin mRNA 的活化69 貳、LPS 在轉錄層次調控resistin mRNA 表現72 參、LPS 並不是經由自由基以活化resistin mRNA 72 肆、PI3K 和ERK pathway 參與LPS 對resistin mRNA 的活化作用73 伍、NF-κB 參與LPS 對resistin mRNA 的活化74 第五節結論74 第五章H2O2對巨噬細胞和單核球細胞resistin mRNA表現的影響76 第一節動機與假說77 第二節材料與方法77 第三節結果77 壹、H2O2對人類周邊血液單核球resistin mRNA表現的影響77 一、THP-1 細胞株77 二、人類周邊血液單核球細胞77 貳、H2O2resistin mRNA參、H2O2經由什麼路徑誘發resistin mRNA表現？77 一、JNK抑制劑：SP600125 對H2O2活化細胞resistin mRNA表現之 影響78 二、p38 kinase抑制劑：SB203580 對H2O2誘發細胞resistin mRNA表 現的影響78 三、NF-κB：CAPE抑制H2O2對THP-1 細胞resistin mRNA的表現78 肆、LPS和H2O2以不同調控方式增加單核球細胞resistin mRNA表現78 第四節討論80 壹、H2O2誘發單核球細胞resistin mRNA表現80 貳、H2O2在轉錄層次調控resistin mRNA 表現80 參、H2O2經由NF-κB活化resistin mRNA表現80 第五節結論80 第六節綜合討論81 壹、LPS和H2O2經由不同機制誘發細胞resistin mRNA表現81 貳、Resistin 在發炎反應和氧化壓力引起之胰島素所扮演的角色81 第六章圖表82 第七章參考文獻120 圖表目錄 Table 3-1. Diet composition 82 Table 3-2. Plasma glucose, triacylglycerol(TG), insulin, and leptin concentrations of the rats. 83 Table 4-1. Plasma glucose, triacylglycerol(TG), insulin, and leptin concentrations of the rats. 84 Figure 2-1. LPS stimulation of monocytes activates signaling pathways and transcription factors. 85 Figure 3-1. Effects of a fat-free or a high-fat diet on ob mRNA expression in rat adipose tissue. 86 Figure 3-2. Plasma lipoproteins analysis by agarose gel electrophoresis. 87 Figure 3-3. Dose and time course effect of TRL on ob mRNA expression in 3T3-L1 adipocytes. 88 Figure 3-4. TRL suppresse insulin-induce ob mRNA expression in 3T3-L1 adipocytes. 89 Figure 4-1. Quantification of GAPDH mRNA in RAW264.7 cells. 90 Figure 4-2. Quantification of resistin mRNA in RAW264.7 cells. 91 Figure 4-3. Quantification of TNF-α mRNA in RAW264.7 cells. 92 Figure 4-4. LPS induces resistin mRNA expression in RAW264.7 cells in a dose-dependent manner. 93 Figure 4-5. LPS induces resistin mRNA expression in RAW264.7 cells in a time-dependent manner. 94 Figure 4-6. LPS effects on resistin and TNF-α mRNA levels in mice Kuffper cells. 95 Figure 4-7. Actinomycin D effects on resistin mRNA levels in RAW264.7 cells. 96 Figure 4-8. LPS induced increase of resistin mRNA is not mediated by H2O2 in RAW264.7 cells. 97 Figure 4-9. Effects of dexamethasone on resistin mRNA levels in response to LPS in RAW264.7 cells. 98 Figure 4-10. Effects of genesitin on resistin mRNA levels in response to LPS in RAW264.7 cells. 99 Figure 4-11. Effects of 15d-PGJ2 on resistin mRNA levels in response to LPS in RAW264.7 cells. 100 Figure 4-12. Effects of ciglitazone on resistin mRNA levels in response to LPS in RAW264.7 cells. 101 Figure 4-13. Effect of pioglitazone on resistin mRNA levels in response to LPS in RAW264.7 cells. 102 Figure 4-14. Effects of SP600125 on resistin mRNA levels in response to LPS in RAW264.7 cells. 103 Figure 4-15. Effects of SB203580 on resistin mRNA levels in response to LPS in RAW264.7 cells. 104 Figure 4-16. Effects of Ro318220 on resistin mRNA levels in response to LPS in RAW264.7 cells. 105 Figure 4-17. Effects of U0126 on resistin mRNA levels in response to LPS in RAW264.7 cells. 106 Figure 4-18. Effects of Ly294002 on resistin mRNA levels in response to LPS in RAW264.7 cells. 107 Figure 4-19. Effects of CAPE on resistin mRNA levels in response to LPS in RAW264.7 cells. 108 Figure 4-20. LPS induces translocation of p50 sbunit to nuclear in RAW264.7 cells. 109 Figure 5-1. H2O2 induces resistin mRNA expression in THP-1 cells in a dose-dependent manner. 110 Figure 5-2. H2O2 induces resistin mRNA expression in THP-1 cells in a time-dependent manner. 111 Figure 5-3. H2O2 effects on resistin mRNA levels in human PBMC cells. 112 Figure 5-4. Effects of actinomycin D on resistin mRNA levels in THP-1 cells. 113 Figure 5-5. Effects of SP600125 on H2O2 induced increase of resistin mRNA in THP-1 cells. 114 Figure 5-6. Effects of SB203580 on resistin mRNA levels in response to H2O2 in THP-1 cells. 115 Figure 5-7. H2O2 induced increase of resistin mRNA in THP-1 cells is blocked by CAPE. 116 Figure 5-8. H2O2 induces translocation of p50 sbunit to nuclear in THP-1 cells. 117 Figure 5-9. H2O2 and LPS effect on resistin and TNF-α mRNA levels in human PBMC cells. 118 Figure 5-10. Effect of H2O2 and LPS on resistin and TNF-α mRNA levels in RAW264.7 cells. 119 | |
| dc.language.iso | zh-TW | |
| dc.subject | 單核球細胞 | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | 胰島素阻抗素 | zh_TW |
| dc.subject | 過氧化氫 | zh_TW |
| dc.subject | 脂多醣 | zh_TW |
| dc.subject | 瘦素 | zh_TW |
| dc.subject | ob 基因 | zh_TW |
| dc.subject | 脂肪細胞 | zh_TW |
| dc.subject | 脂肪細胞素 | zh_TW |
| dc.subject | monocyte | en |
| dc.subject | adipokines | en |
| dc.subject | adipocyte | en |
| dc.subject | TRL | en |
| dc.subject | ob gene | en |
| dc.subject | leptin | en |
| dc.subject | LPS | en |
| dc.subject | H2O2 | en |
| dc.subject | resistin | en |
| dc.subject | macrophage | en |
| dc.title | 脂肪細胞素表現調控之探討：
1.富含三酸甘油酯脂蛋白對脂肪細胞ob基因表現之影響 2.LPS和H2O2對巨噬細胞和單核球細胞resistin mRNA表現之影響 | zh_TW |
| dc.title | Studies on the expression and regulation of adipokines：
1. Triacylglycerol-rich lipoproteins effects on ob gene expression in adipose cells. 2. LPS and H2O2 effects on resistin mRNA expression in macrophages and monocytes. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 黃伯超,吳文惠,張淑芬,黃青真,蕭寧馨,陳惠玲 | |
| dc.subject.keyword | 脂肪細胞素,脂肪細胞,ob 基因,瘦素,脂多醣,過氧化氫,胰島素阻抗素, 巨噬細胞, 單核球細胞, | zh_TW |
| dc.subject.keyword | adipokines,adipocyte,TRL,ob gene,leptin,LPS,H2O2,resistin,macrophage,monocyte, | en |
| dc.relation.page | 158 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-27 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 微生物與生化學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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