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博碩士論文 etd-0618114-155718 詳細資訊
Title page for etd-0618114-155718
論文名稱
Title
果糖攝取在大鼠孤立束核血壓調控機制之探討
The role of consumption of fructose on blood pressure in the nucleus tractus solitarii
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
76
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2014-07-04
繳交日期
Date of Submission
2014-08-26
關鍵字
Keywords
葡萄糖轉運蛋白第五型、果糖、一氧化氮、感壓反射、交感神經活性、孤立束核
baroreflex, fructose, sympathetic nerves activity, nucleus tractus solitarii, glucose transporter five, nitric oxide
統計
Statistics
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The thesis/dissertation has been browsed 5731 times, has been downloaded 54 times.
中文摘要
代謝疾病症候群是導致國人死亡的原因之一。近年來不論在臨床或基礎醫學研究中都發現攝取果糖可能會導致代謝症候群,包含有高血脂症,高血糖,第二型糖尿病和高血壓等疾病。果糖進入體內會先在肝臟中形成三酸甘油酯儲存,並且果糖是高能量原料會在肝臟中促使重新合成三酸甘油酯。根據研究報導攝取高濃度果糖會導致血中三酸甘油酯顯著增加及肝臟中三酸甘油酯堆積,並且先前研究亦證實攝取高濃度果糖會促使血壓上升、交感神經活性活化以及感壓反射敏感性減弱、一氧化氮合成酶表現下降。有趣的是,在先前研究發現在肝臟、小腸中果糖會藉由葡萄糖轉運系統中的葡萄糖轉運蛋白第五型和第二型來進入血液及組織內,另外也發現當給予果糖時會促使神經元細胞中的葡萄糖轉運蛋白第五型和第二型表現。因此根據上述研究文獻,我們提出研究假說: 攝取果糖誘導高血壓的發展,果糖可能是刺激了三酸甘油酯的產生,或是刺激了在孤立束核中的葡萄糖運送蛋白的過度表現而去啟動了交感神經活性而造成高血壓。因在中樞神經系統中對於果糖是如何引起交感神經系統過度激活和如何造成一氧化氮合成酶的功能異常而導致高血壓發生的作用機制尚不清楚。利用雄性正常血壓的WKY (Wistar Kyoto)大鼠給予10%果糖水一週,並在這一週內每天測量交感神經活性和感壓反射敏感性以及內生性一氧化氮在孤立束核內的含量,同時利用了DHE 染色、即時聚合酶鏈鎖反應、免疫墨點法分析蛋白質表現量。 我們的研究結果顯示:攝取果糖顯著性的增加了收縮壓、交感神經活性。有趣的是,我們發現攝取果糖一天到七天這期間中腦脊髓液中的果糖濃度有顯著上升且孤立束核中的一氧化氮含量顯著的減少的現象。我們利用胃灌給予三酸甘油酯抑制劑合併給予攝取果糖一週的大鼠中發現可去減弱因果糖造成的血壓上升的情形和血液中的三酸甘油酯濃度三酸甘油酯抑制劑卻無法去改善了因果糖所造成的交感神經過度活化和中樞一氧化氮濃度下降的效應,因此推論在果糖誘發高血壓的早期可能是果糖造成了葡萄糖轉運蛋白第五型合成量增加導致運送果糖進入腦部所造成的。進一步的研究結果顯示攝取果糖一到七天的大鼠的確會增強了孤立束核內葡萄糖轉運蛋白第五型的表現,同時我們利用500M果糖去培養神經元細胞發現果糖會造成神經元細胞中的葡萄糖轉運蛋白第五型和糖化終產物受體、活性氧化物的過度表現進而抑制了蛋白質激酶B及神經元一氧化氮合成酶的活性下降導致一氧化氮的產生量顯著減少。在本研究中結論為,攝取果糖後會促使葡萄糖轉運蛋白第五型過度表表現,而使糖化終產物受體產生增加並誘導了活性氧化物生成,導致蛋白質激酶B 磷酸化減少,使神經元一氧化氮合成酶活性降低,進而使一氧化氮產量下降,造成了神經系統的傷害而使血壓調控失去平衡 最後造成血壓的上升。
Abstract
Metabolic syndrome is one of the leading cause of death. In clinical and previous studies demonstrated that fructose consumption will induce metabolic syndrome such as hyperlipidemia, hyperglycemia, type 2 diabetes mellitus and hypertensive diseases. However, fructose is primarily metabolized through triglyceride synthesis in the liver and that use as an energy source by de novo lipogenesis. To the best of our knowledge, high fructose intake led to blood triglyceride increase significantly and accumulation of triglyceride in the liver. Several studies showed that administration of fructose significantly increase systolic blood pressures (SBP), renal sympathetic nerves activity (RSNA) and significantly decreased baroreflex sensitivity, nitric oxide synthase expression. Previous studies found that fructose uses glucose transport system and is transported into blood by glucose transporter five (GLUT5) and glucose transporter two (GLUT2) in the liver and small intestine. Simultaneous finding, GLUT5 and GLUT2 expression increased significantly in neuronal cell by administration of fructose. Therefore, we postulated that fructose may induces the development of hypertension which is either stimulus for triglyceride or glucose transporters and that is involved in triggering sympathetic overactivation in the nucleus tractus solitarii(NTS). However, the mechanisms of the overactivation in the brain that cause dysfunction of NO in fructose-induced hypertension remained unclear. Male WKY (Wistar Kyoto) rats were fed with 10% fructose water for one week. Systolic blood pressures (SBP), renal sympathetic nerves activity, baroreflex sensitivity and endogenous nitric oxide level in the NTS were determined. Quantitative PCR and immunoblotting analyses were used to quantify gene and protein expression levels. Our data showed that sympathetic nerve activity and systolic blood pressures (SBP) increased significantly. Interestingly, the fructose concentration in the CSF was significantly increased and NO level in the NTS was significantly decreased after administration of fructose for day1 until day7. These changes are blunted by oral gavage of PF-04620110 (DGAT1 inhibitor) decrease level of SBP and triglyceride however, PF-04620110 were not improves SNA and center NO level in the fructose fed rats at day7. Therefore, fructose may be enhancing GLUT5 synthesis and that perhaps transport fructose into brain in the early stage of fructose inducer pressor. The results showed consumption of fructose enhance GLUT5 expression in the NTS of fructose fed rats at day1~day7. Simultaneously, Fructose (500M) treatment induced GLUT5-RAGE-ROS and reduced AKT-nNOS-NO signaling pathway in the PC12 neuronal cell. In conclusion, fructose through GLUT5-RAGE overexpression induces ROS generation in the NTS, which will lead to AKT-nNOS-NO signaling pathway and impairment cause hypertension.
目次 Table of Contents
論文審定書…………………………………………………………….…………....…i
致謝…………………………………………………………………………….......…ii
摘要……………………………………………………………......…………....…iii-iv
Abstract………………………………………………………………...................v-vii
Abbreviations…………………………………………………….....…….…......…viiiContents………………………………………………………………..…..............ix-x
Introduction
1. Soft drinks and disease………………………………….………...........1-2
2. Metabolic effects of dietary fructose on risk factors for hypertension…………...2-3
3. Blood pressure regulator, sympathetic nervous activity…………………........….3-6
4. The effect of fructose on risk factors for BP regulation and sympathetic nervous activity………………………………………….……………………………….…...6-7
5. Baroreflex sensitivity………………………………………………………….….7-9
6. Cardiovascular regulation in brainstem nuclei………………………………......9-10
7. Metabolic effects of dietary fructose ………………….………………..…..10-11
8. Effect of fructose in the neuronal cell…………................................................11-12
9. Fructose transporter…………………………………………………………....12-14
10. Metabolic syndrome and fructose-fed animal mod…………………….……14-15
Hypothesis and specific aims……………………………………………………..16
Materials and methods………………………………………………………….17-24
Results
1.The fructose intake significantly increased in the fructose fed rats………………………………………………………………………………...25-26
2.Consumption of fructose induced elevation blood pressure and CSF fructose in early stage of fructose fed rat……………………………………………………….......26-27
3.Consumption of fructose induced changes in cardiovascular 4.parameters.……………………………………………...........…………………27-28
5.PF04620110 (DGAT1 Inhibitor) significant attenuate BP and TG, but not the RSNA after consumption of fructose for 7 days…………………………………..……..28-29
6.Effects of fructose on the glucose transporter 5 mRNA and protein high expression in the NTS of fructose fed rats.……….…………………………...……………...29-30
7.Fructose overexpression of glucose transporter 5 (GLUT5) enhances RAGE-ROS pathway and defect AKT-nNOS-NO signaling pathway in the PC12 neuronal cell………………………………………………………………………………...30-31
Discussion……………………………………………………………...…………32-39
Conclusion…………………………………………………………………………...40
Future perspectives……………………………………………………….…...........41
References…………………………………………………………………...…...42-49
Figures and legends………………………………………………...……………50-61
Supplemental Figures and Figure legends……………………………………..62-65
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