臺灣博碩士論文加值系統

第二型糖尿病主要是因胰島素阻抗而造成高血糖和代謝異常等症狀，當糖尿病患者長期處於高血糖的狀態時，會產生過多的氧化壓力並對組織器官造成傷害，隨即發展成神經退化性疾病等糖尿病併發症。神經退化性疾病可能是細胞骨架和神經傳導物質異常導致，並且細胞骨架恆定也牽涉到脂肪細胞的胰島素作用、第四型葡萄糖轉運蛋白轉位(glucose transport type 4; GLUT4)和脂肪油滴的運送等代謝功能。Collapsin response mediator protein 2 (CRMP2)是一種調控細胞骨架的動態平衡與運輸囊泡的蛋白質。本實驗室先前研究結果指出，CRMP2在大腸癌合併糖尿病的患者表現較低，在脂肪細胞分化過程中也會下降，並影響油滴累積。此外，已知神經細胞中CRMP2的活性受到glycogen synthase kinase-3β (GSK-3β) 之調節，進而影響微管等細胞骨架恆定以協助神經細胞發育；而GSK-3β也是胰島素訊息傳遞路徑中關鍵分子，對於GLUT4轉位扮演重要角色。承上，我們假設CRMP2可能在脂肪細胞中參與GLUT4轉位等能量代謝的調控機制。因此本論文主要探討CRMP2對於脂肪細胞能量代謝、細胞分化和細胞骨架之影響，並且研究葡萄糖濃度對於CRMP2與脂肪細胞代謝等功能的影響。本研究發現CRMP2在脂肪細胞分化過程中持續保持活化狀態。過量表現CRMP2會降低CCAAT/enhancer binding protein α (C/EBP-α)、peroxisome proliferator-activated receptor gamma (PPAR-γ)和fatty acid binding protein 4 (FABP4)等脂肪細胞特有基因之表現量；同時也會降低acetyl CoA carboxylase (ACC)和fatty acid synthase (FAS)等脂肪酸生成酵素蛋白表現量，並且增加肌動蛋白絲的聚合作用，進而讓油滴堆積減少抑制脂肪細胞分化。抑制CRMP2表現則會產生相反結果，所以CRMP2確實參與脂肪生成和細胞分化等功能。除此之外，正常葡萄糖濃度(100 mg/dL)會使CRMP2、GLUT4、PPAR-γ和FABP4等脂肪基因表現量上升，並使基礎葡萄糖攝取能力增加約60%，但卻會減少脂肪油滴堆積量，因此葡萄糖濃度會調控CRMP2表現量並影響脂肪細胞葡萄糖攝取和油滴堆積等能力。然而正常濃度葡萄糖並不會影響CRMP2 mRNA表現和蛋白質半衰期。綜合本研究結果，葡萄糖濃度影響CRMP2表現量，因而調控葡萄糖攝取和油滴堆積功能，並增加細胞骨架的聚合，降低脂肪細胞分化和脂質合成。綜合上述，本研究推測高血糖可能影響CRMP2使脂肪組織代謝功能異常並參與糖尿病併發神經退化性疾病的致病機制。

Diabetes mellitus is a metabolic abnormality defined by hyperglycemia resulting from defects in insulin action and/or insulin secretion. Diabetic patients with long-term hyperglycemia are susceptible to develop multiple complications and neurodegenerative diseases due to hyperglycemia-resulted oxidative stress and damage. Cytoskeleton is abnormally assembled and neurotransmission is impaired in neurodegenerative diseases. Moreover, alterations in cytoskeleton dynamics have been implicated in insulin action, glucose transporter type 4 (GLUT4) translocation and trafficking of lipid droplets in adipocytes. Collapsin response mediator protein 2 (CRMP2) regulates neurite outgrowth through mediating microtubules dynamics, which is regulated by glycogen synthase kinase-3β (GSK-3β), the important mediator in the signaling of insulin and GLUT4 translocation. Accordingly, we hypothesized that CRMP2 may be involved in energy homeostasis and thus adipocyte differentiation (adipogenesis). The aim of this study is to investigate expression profile and effects of CRMP2 on glucose and lipid metabolism in adipogenic process of 3T3-L1 pre-adipocytes under high (hyperglycemia) or low (normoglycemia) glucose environment. Our results showed that CRMP2 overexpression in mature adipocytes led to reduced lipids accumulation and decreased expression of fatty acid synthesis enzyme (acetyl CoA carboxylase, ACC and fatty acid synthase, FAS) and adipogenesis marker peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer binding protein α (C/EBP-α) and fatty acid binding protein 4 (FABP4), while actin filament polymerization is increased. In contrast, knockdown of CRMP2 expression attenuated the above effects. Besides, CRMP2 expression and basal glucose uptake activity were significantly increased in cells under normoglycemic (100 mg/dL) condition. Although lipids contents were reduced in cells exposed to low glucose, expression of PPAR-γ, FABP4 and GLUT4 were elevated. Nevertheless, glucose levels did not affect CRMP2 mRNA levels and proteasomal degradation in adipogenic process. The above results suggest that under physiological glucose environment, the increased CRMP2 expression may result in upregulation of FABP4, PPAR-γ and GLUT4 that facilitates adipocyte differentiation as well as glucose uptake. In addition, the CRMP2-mediated decrease of fatty acid synthesis enzymes and adipogenesis markers and increase of cytoskeleton polymerization result in the reduced lipid accumulation. The above results suggest that CRMP2 may participate in diabetic pathogenesis and diabetic neuropathy through mediating lipid and glucose metabolism in response to external nutrient condition.

目錄
中文摘要 i
Abstract iii
目錄 v
壹、縮寫表 1
貳、緒論 3
一、糖尿病 3
1. 糖尿病流行病學 3
2. 糖尿病的定義與臨床症狀 3
3. 糖尿病診斷 4
4. 糖尿病分型 5
5. 糖尿病和阿茲海默症(Alzheimer's disease; AD)之關連性 6
二、脂肪組織(adipose tissue) 7
1. 脂肪組織介紹 7
2. 脂肪組織和代謝症候群(metabolic syndrome) 8
3. 脂肪細胞分化(adipocyte differentiation) 9
三、Collapsin response mediator protein 2 (CRMP2) 12
1. CRMP2蛋白結構 12
2. CRMP2生理功能 13
3. CRMP2活性之調控 14
4. CRMP2與疾病相關性 15
四、脂肪油滴 16
1. 油滴生合成 16
2. 中性脂質生成 17
3. 脂肪油滴的融合和運輸 18
五、第四型葡萄糖轉運蛋白(GLUT4) 19
1. GLUT4蛋白結構 19
2. 胰島素對GLUT4轉位之調控 19
3. 細胞骨架對於GLUT4運輸之關聯 20
4. 肥胖和第二型糖尿病對GLUT4之異常調控 21
參、研究動機與目的 22
肆、實驗方法 24
一、3T3-L1脂肪細胞培養(cell culture of 3T3-L1 cell) 24
1. 細胞繼代培養 24
2. 解凍細胞 25
3. 細胞誘導分化(cell differentiation) 25
4. 高濃度葡萄糖或低濃度葡萄糖細胞培養(cell culture under high or low glucose environment ) 25
5. 放線菌酮(cycloheximide)處理 26
二、西方墨點法(Western Blotting) 26
1. 細胞萃取液製備 26
2. 蛋白質定量 26
3. 電泳樣品製備 27
4. 電泳膠片的轉漬與Blocking 27
5. 一級與二級抗體反應與冷光訊號偵測 28
6. 呈色與顯影(color development) 28
四、RT-PCR (reverse transcription-polymerase chain reaction) 29
1. RT (reverse transcription) 29
2. 聚合酶連鎖反應(polymerase chain reaction) 30
3. DNA電泳 30
五、CRMP2質體抽取(CRMP2 plasmid extraction) 30
六、脂肪細胞油滴染色(Oil-Red O staining) 31
七、DNA轉染(DNA transfection) 32
八、免疫螢光染色(immunofluorescence staining) 32
九、siRNA轉染(siRNA transfection) 33
十、測量葡萄糖攝取活性(Measurement of glucose uptake) 34
十一、統計分析 34
伍、結果 35
一、脂肪細胞分化過程中CRMP2表現和活性之情形 35
二、CRMP2對脂肪細胞分化之影響 37
三、CRMP2對脂肪細胞油滴累積之影響 38
四、CRMP2對脂肪細胞脂質生成酵素的影響 38
五、CRMP2對脂肪細胞之細胞骨架之影響 39
六、葡萄糖濃度對CRMP2和脂肪細胞分化影響之情況 41
1. 低濃度葡萄糖(100 mg/dL)培養對脂肪細胞油滴累積之影響 41
2. 低濃度葡萄糖(100 mg/dL)對脂肪細胞分化和CRMP2表現量之影響 42
3. 不同葡萄糖濃度對脂肪細胞中CRMP2降解程度之影響 43
4. 低濃度葡萄糖(100 mg/dL)對脂肪細胞葡萄糖攝取能力之影響 44
陸、討論 46
柒、參考文獻 54
捌、圖表與圖表說明 70
Figure 1. Expression of adipocyte differentiation marker and CRMP2 during adipogenesis in 3T3-L1 cell. 72
Figure 2. Expression of CRMP2 mRNA during adipogenesis in 3T3-L1 cells. 73
Figure 3. Expression of p-CRMP2 Thr-514 and p-GSK-3β Ser-9 phosphorylation during adipogenesis in 3T3-L1 cells. 74
Figure 4. Effects of CRMP2 on adipogenesis marker during adipogensis in 3T3-L1 cells. 78
Figure 5. Effects of CRMP2 on lipid accumulation in mature 3T3-L1 cells. 81
Figure 6. Effects of CRMP2 on lipid synthesis enzymes during adipogensis in 3T3-L1 cells. 84
Figure 7. Effects of CRMP2 on actin filament and lipid droplets (LDs) in mature 3T3-L1 cells. 89
Figure 8. Effect of high (450 mg/dL) or low (100 mg/dL) glucose concentration culture environments on lipid accumulation in mature 3T3-L1 cells. 91
Figure 9. Effect of high or low glucose culture media on expression of CRMP2 and adipocyte differentiation marker during adipogensis in 3T3-L1 cells. 94
Figure 10. Effect of high or low glucose culture media on expression of CRMP2 mRNA during adipogenesis in 3T3-L1 cells. 95
Figure 11. Effect of high or low glucose culture media on distribution of CRMP2 and GLUT4 during adipogensis in 3T3-L1 cells. 97
Figure 12. Effect of various glucose concentrations on degradation of CRMP2 proteins in day 4 3T3-L1 cells. 98
Figure 13. Effect of high or low glucose culture media on glucose uptake ability in mature 3T3-L1 cells. 99
玖、附錄 100
附圖ㄧ、Induction of adipogenesis by a cascade of transcription factors. 100
附圖二、CRMPs family protein sequence 102
附圖三、CRMP2 protein structure 103
附圖四、CRMP2 signaling pathways and functions 104
附圖五、Lipid droplets trafficking 106
附圖六、Tow kinds of Insulin signalling regulates GLUT4 exocytosis 107
附圖七、Map of pTARGET-CRMP2-myc tag 109
附表一、引子序列 110
附表二、siRNA序列 110
附表三、藥品 110

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楊蕙如（2012）。大腸直腸癌合併糖尿病患者CRMP2表現量之研究。中山醫學大學生化暨生物科技研究所碩士論文。
許瑋庭（2013）。脂肪細胞中Collapsin Response Mediator Protein 2蛋白對脂質和葡萄糖代謝之影響。國立陽明大學醫學生物技術暨檢驗學系研究所碩士論文。