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系統識別號 U0026-2501201416461100
論文名稱(中文) 探討骨骼肌中粒線體動態受脂毒性影響粒線體功能與代謝的調節
論文名稱(英文) Mitochondrial dynamics in regulation of mitochondrial function and metabolism in response to lipotoxicity in skeletal muscle
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 1
出版年 103
研究生(中文) 鄭蕙芬
研究生(英文) Huei-Fen Jheng
學號 s58961117
學位類別 博士
語文別 英文
論文頁數 118頁
口試委員 口試委員-王寧
口試委員-蔡亭芬
口試委員-謝達斌
口試委員-任卓穎
口試委員-蔡佩珍
指導教授-蔡曜聲
中文關鍵字 粒線體動態  肥胖  棕櫚酸  肌肉  糖尿病 
英文關鍵字 mitochondrial dynamics  obesity  palmitate  muscle  diabetes 
學科別分類
中文摘要 肥胖性胰島素阻抗是代謝症候群早期重要特徵。同時肌肉粒線體功能缺失被認為參與胰島素阻抗與第二型糖尿病的病程。維持良好粒線體動態對於粒線體與細胞功能十分重要,因此我們假設粒線體動態平衡會因肥胖或過多營養刺激而改變,導致粒線體功能失調,進一步造成肌肉代謝失衡。在本篇第一部分發現,高量的飽和脂肪酸,尤以棕櫚酸(palmitate),會增加粒線體斷裂的型態且造成粒線體上Drp1及Fis1上升,顯示棕櫚酸造成肌肉細胞粒線體分裂。透過基因或化學藥物抑制Drp1可降低棕櫚酸引起的粒線體分裂並減少棕櫚酸造成的粒線體膜電位低下及肌肉細胞葡萄糖攝取降低的情況。此外,在基因性或飲食性肥胖的老鼠肌肉組織中存有較短小的粒線體,也呈現較多粒線體分裂機制所需的蛋白質。抑制粒線體分裂可改善肥胖老鼠肌肉與全身對胰島素的感受性。另一方面,粒線體動態與自噬功能在粒線體生命週期中,共同維持粒線體的品質。我們假設過多棕櫚酸刺激而失衡的粒線體動態會促進自噬功能,藉此清除失能粒線體。在本篇第二部分,我們發現棕櫚酸可刺激自噬蛋白(LC3)第二型蛋白質表現,同時氯奎 (chloroquine)可以增強棕櫚酸造成的LC3-II累積,顯示棕櫚酸可以促進自噬體 (autophagosome)產生。出乎意料的,p62 蛋白質隨者棕櫚酸作用時間越長,累積的現象越加明顯。但是,透過抑制Drp1減少粒線體分裂可回復因棕櫚酸增加的LC3-II。這些結果顯示雖然棕櫚酸會抑制自體吞噬的過程,但粒線體分裂會促進LC3-I 和LC3-II在細胞的表現量。另一方面,透過甲基腺嘌呤 (3-MA)可改善棕櫚酸造成的粒線體斷裂,這個現象與Drp1 S637磷酸化現象增強有關。總結本篇論文,我們發現在高量棕櫚酸刺激下,會導致粒線體動態與自噬功能異常,藉著失衡的粒線體功能參與肥胖與第二型糖尿病中肌肉產生胰島素阻抗的病程。
英文摘要 Obesity-induced insulin resistance is the major character in the early stage of metabolic syndrome. Mitochondrial dysfunction in skeletal muscle has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. Since mitochondrial dynamics plays an important role in maintenance of mitochondrial and cellular function, we hypothesize that the balance of mitochondrial dynamics is altered due to stress from obesity and nutrient excess, further contributing to increases in mitochondrial dysfunction and metabolic deterioration in skeletal muscle. In the first part of this study, we found that excess saturated fatty acid, especially palmitate (PA), induced mitochondrial fission, as evidenced by mitochondrial fragmentation and increases in mitochondria-associated Drp1 and Fis1 in muscle cells. The reduction of PA-induced mitochondrial fragmentation by genetic or pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial depolarization, and decreased insulin resistance in C2C12 cells. Moreover, both genetic and diet-induced obese mice had smaller and shorter mitochondria, and showed increased molecular machinery of mitochondrial fission in the skeletal muscle. Inhibition of mitochondrial fission both improved muscle insulin signaling and systemic insulin sensitivity of obese mice. In mitochondrial life cycle, both mitochondrial dynamics and autophagy contribute to maintain mitochondrial quality. We hypothesize that imbalance of mitochondrial dynamics increases autophagy in response to excess PA, thus removing dysfunctional mitochondria. In the second part, we found that PA increased microtubule-associated protein light chain 3 (LC3)-II protein levels in myoblasts. Enhancement of LC3-II accumulation by chloroquine indicated an increase in autolysosome formation upon PA treatment. Surprisingly, with the increased time of PA treatment, the p62 protein levels were accumulated. However, reduction of mitochondrial fission by inhibition of Drp1 suppressed PA-increased LC3-II protein levels. These data indicated although PA suppresses autophagic flux, mitochondrial fission promotes LC3-I and LC3-II protein levels. Moreover, reduction of LC3 conversion by 3-methyladenine (3-MA) attenuated PA-induced mitochondrial fragmentation, a phenomenon which is associated with increases in Drp1 S637 phosphorylation. Taken together, our present data suggest the imbalance in mitochondrial dynamics and autophagy induce by excess PA, may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.
論文目次 Abstract III
Abstract in Chinese V
Acknowledge VI
Contents VII
Table contents VIII
Figure contents IX
Abbreviations XI
Chapter 1--Introduction 1
Mitochondrial fusion 1
Mitochondrial fission 2
Regulation of mitochondrial dynamics 3
Biological functions of mitochondrial dynamics 4
Chapter 2-- Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle 6
Abstract 6
Introduction 8
Material and methods 11
Results 15
Discussion 23
Perspective 30
Chapter 3-- Mitochondrial fission regulated autophagy by increasing LC3-II expression 34
Abstract 34
Introduction 35
Material and methods 37
Results 38
Discussion 40
Summary and suggestions for future research 44
References 47
Tables 55
Figures 56
Supplemental data 77
Appendices 79
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