Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/52052
標題: Enhancement of caffeic acid on protein glycation and the modulation of advanced glycation endproducts on glucose uptake in adipocytes
咖啡酸對蛋白質醣化之促進作用及高度醣化終產物調控脂肪細胞葡萄糖吸收之研究
作者: 黃筱雯
Huang, Hsiao-Wen
關鍵字: advanced glycation endproducts
高度醣化終產物
caffeic acid
insulin resistance
methylglyoxal
oxidation
protein glycation
咖啡酸
胰島素阻抗
活性雙羰基化合物
氧化
蛋白質醣化作用
出版社: 食品暨應用生物科技學系所
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摘要: 糖尿病患體內高血糖之生理環境促進醣化反應,進而增加高度醣化終產物 (advanced glycation endproducts, AGEs) 之生成,為高血糖誘發慢性併發症之主要因素,導致糖尿病慢性併發症之小血管病變如神經病變、腎臟病變及視網膜病變與大血管病變如心血管疾病。此外,AGEs 亦可能與 T2D 患者普遍存在之胰島素阻抗的發生有關。本論文分為兩大研究主題:(一) 酚酸化合物對活性雙羰基化合物誘發蛋白質醣化與 AGEs 生成之影響;(二) AGEs 對脂肪細胞葡萄糖吸收之影響,與其造成胰島素阻抗之可能機制。 (一) 醣化作用與 AGEs 生成,為形成糖尿病併發症之關鍵因素。酚酸化合物普遍存在良好之抗氧化性,大部分研究亦指出其具良好之生理活性,然而其是否具有抑制蛋白質醣化修飾之潛力卻仍少有文獻探討。本研究以活性雙羰基化合物 (reactive carbonyl species, RCS) 醣化小牛血清蛋白 (bovine serum albumin, BSA) 為模式,探討酚酸化合物 caffeic acid (CA)、 ferulic acid (FA)、m-coumaric acid (mCOA) 及chlorogenic acid (CHA) 對於醣化反應之影響。蛋白質電泳及AGEs特異性螢光分析顯示,CA可隨劑量顯著促進 methylglyoxal (MG) 所誘導之BSA醣化 (p < 0.05);介入抗氧化劑 (alfa-lipoic acid 及 glutathione) 或金屬螯合劑 (EDTA) 可降低上述 CA 之促醣化效應。電子自旋共振光譜 (electron paramagnetic resonance, EPR) 分析顯示,CA可加成MG之自由基生成,推測此促氧化性可能與其促醣化作用有關。本研究另選取胎牛血清 (fetal bovine serum, FBS) 為醣化目標蛋白,於 37 度無菌狀態下分別與 MG、CA 及 aminoguanidine (AG) 反應九天以製備不同醣化程度之 FBS,並測定上述醣化FBS與單核球 (THP-1 cells)、巨噬細胞 (RAW 264.7 cells) 或臍靜脈內皮細胞 (human umbilical vein endothelial cell, HUVEC) 培養後所引發之相關傷害效應。結果顯示,MG 與 CA (MG/CA-FBS) 共反應後所形成之醣化 FBS:(1) 可顯著誘發THP-1 單核球之促發炎因子 TNF-alfa 與 IL-1beta 基因表現,並促使胞內活性氧分子生成; (2) 促進 RAW 264.7 巨噬細胞 TNF-alfa 分泌;(3) 造成 HUVECs 臍靜脈內皮細胞 DNA 損傷、AGEs 膜受器與血管黏附因子 VCAM-1 及 ICAM-1基因表現。再者,與 MG-FBS組比較,MG/CA-FBS 可顯著提昇單核球對血管內皮細胞之移行作用,而此移行效應在MG/AG-FBS共培養之單核球則有明顯降低的現象。本研究結果顯示,於 MG 醣化蛋白質模式下,CA 可促進 MG之蛋白質醣化與促氧化作用,並誘發相關動脈硬化致病因子之表現,然而此負面效應於體內是否有類似現象,乃待進一步探討。 (二) 胰島素阻抗 (insulin resistance) 與AGEs 生成為引發糖尿病之關鍵因子。本研究以活性雙羰基化合物-glyoxal (GO) 醣化蛋白質為模式,探討其衍生之 GO-derived AGEs (GO-AGEs) 產物對於骨骼肌細胞 (C2C12 cells) 或脂肪細胞 (3T3-L1 cells) 葡萄糖吸收之影響。結果顯示,在胰島素存在下 GO-AGEs 可誘導 3T3-L1 脂肪細胞之葡萄糖吸收作用,延長作用時間則可促進脂肪滴生成;於相同劑量下對 C2C12 cells 則具有抑制效應。胰島素訊息調控機轉顯示,GO-AGEs 可抑制 insulin receptor substrate 1 (IRS1) 於 Ser307 位置之磷酸化作用,繼而活化 Akt (protein kinase B),以調控下游 GLUT4 蛋白質表現,促進脂肪細胞葡萄糖吸收。MAPK (mitogen-activated protein kinase) family 中,p38 MAPK 活化及 JNK 之抑制亦可能在上述作用機轉中扮演關鍵的角色。GO-AGEs 促進脂肪細胞之葡萄糖吸收作用可能與其活化胰島素訊息傳遞路徑及調控 MAPKs pathway 有關。再者,GO-AGEs 可顯著誘發 3T3-L1 cells 促發炎細胞激素 IL-6 基因表現,並造成胞內活性氧 (reactive carbonyl species, ROS) 生成。實驗結果顯示,AGEs 可特異性誘導脂肪細胞葡萄糖吸收,並加速其胞內脂肪滴生成,而促進其胞內氧化壓力與發炎反應之發生,可能導致胰島素阻抗,推測好發於肥胖之第二型糖尿病患者,其胰島素阻抗現象可能與其體內 AGEs 生成有關。 綜合上述研究成果,AGEs 於糖尿病與其併發症之發生過程中可能扮演舉足輕重之角色,飲食中若可避免促醣化因子之攝取達到降低AGEs之生成將有可能延緩或預防糖尿病與其併發症之發生。
Diabetes mellitus is a chronic disease characterized by hyperglycemia. Glycation, the non-enzymatic reaction of reducing sugars with amino groups is increased in hyperglycemia environment, followed by an acceleration of the formation of advanced glycation endproducts (AGEs). Increasing evidences indicate that AGEs are well-recognized pathogenic factors of diabetes and its complications affecting macro- and micro-vasculature, heart, kidneys, eyes, and nerves. Moreover, AGEs might also be involved in the development of insulin resistance, the main symptom of type 2 diabetes (T2D). There are two topics included in this thesis: (1) Effect of phenolic acids on methylglyoxal-induced protein glycation and the formation of AGEs; (2) Effect of AGEs on glucose uptake in 3T3-L1 cells, and the proposed mechanism in pathogenesis of insulin resistance. In the first topic, glycation and the formation of AGEs have been causally implicated in the pathogenesis of diabetic complication. Phenolic acids are of current interest in research due to their important biological and pharmacological function, which is attributed to their antioxidant properties. Until now, the literature data concerning the effect of phenolic acids in preventing proteins modification have been limited. In this study, the model of methylglyoxal (MG)-mediated glycation of bovine serum albumin (BSA) was utilized to investigate the effect of phenolic acids (caffeic acid, CA; ferulic acid, FA; m-coumaric acid, mCOA; chlorogenic acid, CHA) on protein glycation. Data from SDS-PAGE and AGE-related fluorescence showed that MG-mediated protein glycation was dose dependently enhanced by CA, whereas antioxidant (alfa-lipolic acid and glutathione) or metal ion-chelating agent (EDTA) treatment was effective in the prevention of these proglycation events. Electron paramagnetic resonance (EPR) spectra showed that CA increased the production of MG-mediated free radicals. These observations suggested that the proglycation mechanism of CA was associated to its pro-oxidative property. Additionally, fetal bovine serum (FBS) was utilized as target protein for evaluating the damaging effect of CA in the cellular model. Different glycated FBS samples were prepared by incubating FBS with MG, CA and aminoguanidine (AGEs inhibitor), respectively, and then they were cultured with THP-1 monocyte, RAW 264.7 macrophage and human umbilical vein endothelial cell (HUVEC). The results indicated that, among glycated FBS samples, MG combined with CA-prepared FBS (MG/CA-FBS) evoked the greatest deleterious responses as follow: (1) inducing proinflammatory cytokine TNF-alfa and IL-1beta gene expression and intracellular ROS production in THP-1 monocyte; (2) stimulating TNF-alfa secretion in RAW 264.7 macrophage; (3) causing DNA damage and inducing gene expression of receptor for AGEs (RAGE) and adhesion molecules VCAM-1 and ICAM-1 in HUVEC. Furthermore, adhesion and transendothelial migration of monocyte to the endothelium were significantly increased by MG/CA-FBS treatment as compared to MG-FBS. Our data show that CA exhibits pro-oxidative and pro-glycative effects during the process of MG-mediated oxidation and glycation, suggesting the disadvantageous role of CA in the progression of diabetes-accelerated atherosclerosis. Our findings may arouse interests in the negative effects of phenolic acids under a high glycotoxin environment. Further study is needed to confirm whether caffeic acid can produce this effect in vivo. In the second topic, insulin resistance and the formation of advanced glycation endproducts (AGEs) are crucial factors in evoking diabetes. In this study, the model of glyoxal (GO)-mediated protein glycation was utilized to investigate the effect of GO-derived AGEs (GO-AGEs) on glucose uptake in C2C12 skeletal muscle cells and 3T3-L1 adipocytes. Results shown that GO-AGEs increased the insulin stimulated glucose uptake and the formation of lipid droplets in 3T3-L1 adipocytes. On the contrary, GO-AGEs inhibited glucose uptake in C2C12 cells. A possible mechanism underlying the distinct action is that GO-AGEs treated-adipocyte caused a decrease in IRS1Ser307 phosphorylation, an increase in Akt activation and GLUT4 protein expression in insulin signaling pathway, which improved the ability for insulin-stimulated glucose uptake in 3T3-L1 cells. Addtionally, p38 MAPK activation and reducing the level of phospho-JNK in MAPK pathway may also play a key role. Therefore, we hypothesized that GO-AGEs might mediate MAPK pathway and activate insulin signaling to increase glucose uptake in 3T3-L1 adipocytes. Furthermore, GO-AGEs significantly induced proinflammatory cytokine IL-6 gene expression and intracellular ROS production. Results obtained in the present study demonstrated that AGEs could specifically induce glucose uptake in adipocyte, and enhance the formation of lipid droplets, intracellular oxidative stress, and inflammation. This suggests that AGEs might participate in the development of insulin resistance. These findings provide a proposed mechanism that the formation of AGEs in vivo might concern the obesity-associated insulin resistance in T2D. In conclusion, AGEs plays a crucial role in diabetes and its complications. Avoiding the dietary ingestion of proglycation factors, thus decreasing the levels of AGEs, might be effective in delaying and preventing the development and progression of diabetes and its complications.
URI: http://hdl.handle.net/11455/52052
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