高脂膳食对淋巴细胞亚群的影响及白藜芦醇的干预作用
发布时间：2019-06-18 14:55
【摘要】：肥胖与炎症性疾病、糖尿病、心血管功能障碍等慢性疾病密切相关。长期高脂膳食可以促进机体能量摄入显著增加，从而导致过剩的能量在体内以脂肪的形式蓄积，并伴有氧化应激和慢性炎性反应的发生。有研究发现高脂膳食饲喂诱导肥胖小鼠的过程中会出现肥胖与肥胖抵抗两种表型。目前还鲜有研究报道高脂膳食诱导肥胖与肥胖抵抗过程中，机体氧化应激对淋巴细胞免疫功能的影响。因此，本文旨在探讨高脂膳食诱导氧化应激影响肥胖与肥胖抵抗两种表型小鼠淋巴细胞亚群能量代谢与凋亡的分子机制，并通过抗氧化剂白藜芦醇的干预，研究其能否通过缓解机体和免疫细胞氧化应激，调节细胞能量代谢，从而缓解机体慢性炎性反应。 1.高脂膳食对肥胖与肥胖抵抗表型氧化还原状态与淋巴细胞亚群的影响 高脂膳食诱导肥胖与肥胖抵抗两种表型。肥胖组血脂水平升高，脾脏抗氧化能力显著降低。肥胖抵抗组较肥胖组血脂水平降低，抗氧化能力有所升高。肥胖组外周血和脾脏CD3+CD4+/CD3+CD8+比值及Tregs细胞含量显著降低，脾脏FoxP3和TGF-β表达显著降低，IL7r表达显著升高。血浆和脾脏TNF-α、IL-1和IL-6水平升高，IL-10水平显著降低，脾脏MMP-9表达显著升高，，PPARγ表达显著降低。MCP-1在脾脏整个过程中的表达无显著性差异。肥胖抵抗组血浆IL-1水平显著增加，脾脏TNF-α和IL-6水平显著增加，其淋巴细胞亚群数量和功能、炎性介质表达与正常组没有显著性差异。0.06%白藜芦醇的添加显著降低肥胖组血脂水平及脾脏MDA含量，减少炎性细胞因子含量和炎性介质表达，增加Tregs细胞相关基因、AhR及其目的基因的表达。0.06%剂量的白藜芦醇作用效果好于0.03%。 2.高脂膳食诱导氧化应激对淋巴细胞亚群的影响 肥胖组血糖、血脂、ROS含量显著增加，抗氧化能力减弱，肥胖与肥胖抵抗脾脏GSTpi1表达显著减少。肥胖抵抗组较肥胖组TAC水平显著升高，血糖、血脂、ROS和MDA含量显著降低。肥胖组外周血和脾脏细胞线粒体膜电位显著降低，肥胖抵抗细胞线粒体膜电位较肥胖细胞显著升高，高脂膳食肥胖外周血和脾脏CD3+CD4+/CD3+CD8+比值，脾脏Tregs细胞含量显著减少，脾脏炎性反应相关基因表达显著升高，肥胖抵抗组淋巴细胞数量与正常组没有显著性差异，脾脏MMP-7和TNF-α的表达较肥胖组显著降低。与肥胖细胞相比，肥胖抵抗细胞ROS含量的显著减少能够抑制高脂膳食氧化应激诱导的细胞凋亡的产生，从而缓解炎性反应。白藜芦醇的添加能够减少免疫细胞ROS含量，缓解氧化应激，进一步减少淋巴细胞凋亡，缓解慢性炎性反应。 3.高脂膳食不同处理时间对糖代谢调节及淋巴细胞亚群的影响 高脂膳食6周开始引起血糖、胰岛素和血脂水平显著增加，抗氧化能力降低，脾脏中CD3+CD4+/CD3+CD8+比值和Tregs细胞含量显著减少，外周血Tregs细胞含量显著降低，13周开始，体重增加，脾脏Tregs细胞含量显著降低。高脂膳食6周后脾脏Nrf2和PI3K表达升高。13周开始，脾脏PI3K和AKT表达显著降低，GSK-3β表达显著升高，抗氧化酶HO-1表达显著降低，炎性细胞因子TNF-α表达显著升高。26周后，肥胖抵抗组胰岛素、血脂水平较肥胖组显著降低，抗氧化能力显著升高，外周血和脾脏CD3+CD4+/CD3+CD8+比值及Tregs细胞含量升高。白藜芦醇添加13周开始增加糖代谢基因GLUT4和SIRT1表达，降低高脂膳食血糖和胰岛素水平，提高淋巴细胞亚群数量，降低脾脏COX-2和GSK-3β表达，添加26周后，脾脏抗氧化酶基因表达增加，缓解机体氧化应激，通过增加淋巴细胞数量，缓解慢性炎性反应。 4.高脂膳食不同处理时间对T、B淋巴细胞氧化还原状态及能量代谢的影响 高脂膳食3周，T、B淋巴细胞转化率显著降低，脾脏T淋巴细胞总抗氧化能力显著升高，T、B淋巴细胞Nrf2、抗氧化酶及PGC-1α表达升高，ATP水平显著升高。B淋巴细胞Na-K-ATPase表达显著升高。6周开始，脾脏B淋巴细胞抗氧化能力显著降低，T、B淋巴细胞Nrf2、抗氧化酶及SIRT1表达降低，T细胞Na-K-ATPase和PGC-1α表达显著降低，线粒体膜电位显著降低，加速细胞ATP水平下降。26周肥胖抵抗组T、B淋巴细胞转化率、抗氧化能力、线粒体膜电位和正常组没有显著性差异。Nrf2及其相关抗氧化基因表达较肥胖组显著升高，T、B淋巴细胞PGC-1α表达、ATP水平显著升高，B淋巴细胞SIRT1表达显著升高。白藜芦醇添加6周开始显著提高脾脏T、B淋巴细胞转化率，促进能量代谢相关基因表达，显著提高细胞ATP水平。添加26周后，T、B淋巴细胞抗氧化基因表达增加，恢复细胞能量代谢，减少细胞凋亡。 5.高脂膳食介导氧化应激对Tregs细胞线粒体生物合成与功能的影响 肥胖组外周血和脾脏Tregs细胞相关基因表达显著降低，ROS含量显著升高，Nrf2及其活化基因表达减少，氧化应激加剧诱使线粒体生物合成和功能相关基因表达降低，Caspase3、DAPK1和Bax表达升高，Bcl-2表达降低，诱导细胞凋亡率增加。肥胖抵抗Tregs细胞相关基因表达较肥胖组升高，抗氧化酶表达显著升高，ROS含量显著降低，从而诱导Tregs细胞能量代谢相关基因表达较肥胖组升高，肥胖抵抗组Tregs细胞凋亡相关基因表达与正常组没有显著差异，较肥胖组相比显著减少。白藜芦醇的添加通过增强Tregs细胞抗氧化酶表达，清除细胞中的ROS，提高Tregs细胞线粒体生物合成与功能，提高细胞能量代谢，从而缓解高脂膳食诱导的Tregs细胞功能损伤。 综上所述，高脂膳食性肥胖诱导ROS过量产生，损伤线粒体生物合成与功能，细胞能量代谢功能障碍是导致淋巴细胞亚群比例失调的一个重要因素，从而加剧机体慢性炎性反应。肥胖抵抗组能够缓解高脂膳食介导的氧化应激与细胞能量代谢障碍，调节淋巴细胞亚群比例。白藜芦醇的添加通过清除过量的ROS，缓解氧化应激，并促进线粒体能量代谢，从而保护淋巴细胞功能，缓解慢性炎性反应。
[Abstract]:Obesity is closely related to chronic diseases such as inflammatory diseases, diabetes, and cardiovascular dysfunction. The long-term high-fat diet can promote a significant increase in the body's energy intake, leading to the accumulation of excess energy in the body in the form of fat and with the occurrence of oxidative stress and chronic inflammatory reactions. It was found that obesity and obesity were resistant to two phenotypes in the process of induction of obese mice by high-fat diet. The effect of oxidative stress on the immune function of lymphocytes in the process of obesity and obesity induced by high-fat diet is rarely reported. Therefore, the aim of this paper is to study the molecular mechanism of the effect of high-fat diet on the energy metabolism and apoptosis of the lymphocyte subsets in the two phenotypes of obesity and obesity, and to study whether it can relieve the oxidative stress of the body and the immune cells by the intervention of the antioxidants, the white and the aloe, The energy metabolism of the cells is regulated, so that the chronic inflammatory reaction of the body is relieved. 1. The effect of high-fat diet on the phenotype of obesity and obesity-resistant phenotype and lymphocyte subpopulation Effect of high-fat diet on obesity and obesity resistance Phenotype. The level of blood lipid in the obese group was increased, and the anti-oxidation ability of the spleen was significant. The decrease of the blood lipid level and the anti-oxidation ability of the obesity-resistant group in the obesity-resistant group The ratio of CD3 + CD4 +/ CD3 + CD8 + and Tregs in the peripheral blood and spleen of the obese group was significantly lower, and the expression of FoxP3 and TGF-2 in the spleen was significantly lower, and the expression of IL7r was significantly lower. The levels of TNF-1, IL-1 and IL-6 in plasma and spleen increased, the level of IL-10 was significantly decreased, the expression of MMP-9 in the spleen was significantly increased, and the expression of PPAR was significantly higher. The expression of MCP-1 in the whole process of the spleen was not significant. There was no significant difference in the level of serum IL-1, the level of TNF-1 and IL-6, the number and function of the lymphocyte subpopulation, the expression of inflammatory mediator and the normal group. The content of A, the content of inflammatory cytokines and the expression of inflammatory mediators were decreased, and the expression of the related genes, AhR and the target genes of the Tregs was increased. 03%.2. high-fat diet induced oxidative stress to lymph node The effects of cell subpopulation on blood sugar, blood lipid, ROS content in obese group, anti-oxidation ability, obesity and obesity resistance to spleen GSTpi 1. The expression of TAC in the obesity-resistant group was significantly higher than that in the obese group, and the blood sugar, blood fat, ROS and MD were significantly increased. The content of mitochondrial membrane in the peripheral blood and the spleen of the obese group was significantly decreased, the mitochondrial membrane potential of the obesity-resistant cells was significantly increased, the content of CD3 + CD4 +/ CD3 + CD8 + in the peripheral blood and the spleen of the high-fat diet was significantly decreased, the content of the spleen Tregs was significantly reduced, and the related groups of the inflammatory reaction of the spleen were significantly reduced. The expression of MMP-7 and TNF-1 in the spleen was significantly higher than that in the normal group, and the expression of MMP-7 and TNF-1 in the spleen was higher than that in the normal group. Obese group is significantly lower. Compared with obese cells, the significant reduction of the content of ROS in obesity-resistant cells can inhibit the production of apoptosis induced by high-fat diet oxidative stress, from the addition of the albinol can reduce the ROS content of the immune cells, relieve the oxidative stress, further reduce the apoptosis of the lymphocytes, chronic inflammatory response.3. Regulation of sugar metabolism by different treatment time of high-fat diet The effects of lymphocyte subpopulation on blood glucose, insulin and blood lipid increased significantly after 6 weeks of high-fat diet, the anti-oxidation ability decreased, the CD3 + CD4 +/ CD3 + CD8 + ratio and Tr in the spleen were decreased. The content of egs cells was significantly decreased, the content of Tregs in peripheral blood was significantly decreased, and body weight gain and spleen Tr were started at 13 weeks. After 6 weeks of high-fat diet, the expression of Nrf2 and PI3K in the spleen increased. At the beginning of 13 weeks, the expression of PI3K and AKT in the spleen significantly decreased, the expression of GSK-3 was significantly increased, the expression of anti-oxidation enzyme HO-1 was significantly decreased, and the expression of TNF-1 in the inflammatory cytokines increased significantly. After a week, the levels of insulin and blood lipid in the obesity-resistant group were significantly lower than that in the obese group, the anti-oxidation ability increased significantly, the CD3 + CD4 +/ CD3 + CD8 + ratio of the peripheral blood and the spleen and the ratio of the CD3 + CD4 +/ CD3 + CD8 + in the peripheral The content of Tregs increased. The expression of GLUT4 and SIRT1 of the glucose metabolism gene was increased by 13 weeks after the addition of the albinol, the blood sugar and insulin level of the high fat diet were decreased, the number of the lymphocyte subpopulations was increased, the expression of COX-2 and GSK-3 in the spleen was decreased, and the anti-oxidation enzyme gene expression of the spleen was increased after 26 weeks. to increase, to relieve the oxidative stress of the body, by increasing the number of lymphocytes, 4. Different treatment time of high-fat diet on T and B lymphocytes The effects of redox state and energy metabolism on the metabolism of high-fat diet for 3 weeks, T, B lymphocyte transformation were significantly reduced, and the total anti-oxidation ability of T-lymphocytes in the spleen was significant. elevated, T, B-lymphocytes Nrf2, antioxidant enzymes and PGC-1 The expression of Na-K-ATPase in B-lymphocytes increased significantly, and the expression of Na-K-ATPase in B-lymphocytes increased significantly. The anti-oxidation ability of B-lymphocytes was significantly decreased at 6 weeks, and the expression of T, B-lymphocytes Nrf2, anti-oxidation enzyme and SIRT1 decreased, and the expression of Na-K-ATPase and PGC-1 in T-cells was decreased. A significant decrease in mitochondrial membrane potential and a decrease in the level of ATP in the accelerated cells. The T, B lymphocyte transformation, anti-oxidation ability, line grain, There was no significant difference between the body membrane potential and the normal group. The expression of Nrf2 and its related anti-oxidation gene was significantly higher than that of the obese group. The expression of PGC-1 in T and B lymphocytes and the level of ATP in the normal group were increased significantly. The expression of SIRT1 in lymphocytes increased significantly. After 26 weeks of addition, the anti-oxidation gene expression of T and B lymphocytes increased, high-fat diet mediate oxidative stress to Tr There was a significant decrease in the expression of the related genes in the peripheral blood and spleen Tregs of the obese group and the content of ROS in the peripheral blood and spleen of the obese group. The expression of Nrf2 and its activated genes decreased, the expression of mitochondrial biosynthesis and function-related genes decreased, and the expression of Caspase3, DAPK1 and Bax increased. The expression of Bcl-2 decreased and the apoptosis rate of the cells increased. The expression of the related genes in the obesity-resistant Tregs was higher than that of the obese group, the expression of the anti-oxidation enzyme was significantly increased, and the ROS content was significantly decreased, so that the expression of the related genes related to the energy metabolism of the Tregs was increased, and the obesity-resistant group Tregs was fine. The expression and expression of apoptosis-related genes There was no significant difference in the normal group, and it was significantly decreased compared with the obese group. The addition of the albinol was enhanced by enhancing the anti-oxidation enzyme expression of the Tregs cell, removing the ROS in the cells, increasing the mitochondrial biosynthesis and function of the Tregs cell, increasing the energy metabolism of the cells, and slowing down. The functional damage of Tregs induced by high-fat diet can be induced. In conclusion, high-fat diet can induce excessive ROS production, damage the synthesis and function of the mitochondria, and the dysfunction of energy metabolism of the cell is the proportion of the lymphocyte subpopulation. An important factor in the regulation is to increase the chronic inflammatory response of the body. The obesity-resistant group can relieve the high-fat diet-mediated oxidation. The inhibition of energy metabolism in the cells and the ratio of lymphocyte subpopulations. The addition of the albinol is by removing excess ROS, relieving oxidative stress, and promoting the generation of mitochondrial energy.
【学位授予单位】：江南大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R151
本文编号：2501572
[Abstract]:Obesity is closely related to chronic diseases such as inflammatory diseases, diabetes, and cardiovascular dysfunction. The long-term high-fat diet can promote a significant increase in the body's energy intake, leading to the accumulation of excess energy in the body in the form of fat and with the occurrence of oxidative stress and chronic inflammatory reactions. It was found that obesity and obesity were resistant to two phenotypes in the process of induction of obese mice by high-fat diet. The effect of oxidative stress on the immune function of lymphocytes in the process of obesity and obesity induced by high-fat diet is rarely reported. Therefore, the aim of this paper is to study the molecular mechanism of the effect of high-fat diet on the energy metabolism and apoptosis of the lymphocyte subsets in the two phenotypes of obesity and obesity, and to study whether it can relieve the oxidative stress of the body and the immune cells by the intervention of the antioxidants, the white and the aloe, The energy metabolism of the cells is regulated, so that the chronic inflammatory reaction of the body is relieved. 1. The effect of high-fat diet on the phenotype of obesity and obesity-resistant phenotype and lymphocyte subpopulation Effect of high-fat diet on obesity and obesity resistance Phenotype. The level of blood lipid in the obese group was increased, and the anti-oxidation ability of the spleen was significant. The decrease of the blood lipid level and the anti-oxidation ability of the obesity-resistant group in the obesity-resistant group The ratio of CD3 + CD4 +/ CD3 + CD8 + and Tregs in the peripheral blood and spleen of the obese group was significantly lower, and the expression of FoxP3 and TGF-2 in the spleen was significantly lower, and the expression of IL7r was significantly lower. The levels of TNF-1, IL-1 and IL-6 in plasma and spleen increased, the level of IL-10 was significantly decreased, the expression of MMP-9 in the spleen was significantly increased, and the expression of PPAR was significantly higher. The expression of MCP-1 in the whole process of the spleen was not significant. There was no significant difference in the level of serum IL-1, the level of TNF-1 and IL-6, the number and function of the lymphocyte subpopulation, the expression of inflammatory mediator and the normal group. The content of A, the content of inflammatory cytokines and the expression of inflammatory mediators were decreased, and the expression of the related genes, AhR and the target genes of the Tregs was increased. 03%.2. high-fat diet induced oxidative stress to lymph node The effects of cell subpopulation on blood sugar, blood lipid, ROS content in obese group, anti-oxidation ability, obesity and obesity resistance to spleen GSTpi 1. The expression of TAC in the obesity-resistant group was significantly higher than that in the obese group, and the blood sugar, blood fat, ROS and MD were significantly increased. The content of mitochondrial membrane in the peripheral blood and the spleen of the obese group was significantly decreased, the mitochondrial membrane potential of the obesity-resistant cells was significantly increased, the content of CD3 + CD4 +/ CD3 + CD8 + in the peripheral blood and the spleen of the high-fat diet was significantly decreased, the content of the spleen Tregs was significantly reduced, and the related groups of the inflammatory reaction of the spleen were significantly reduced. The expression of MMP-7 and TNF-1 in the spleen was significantly higher than that in the normal group, and the expression of MMP-7 and TNF-1 in the spleen was higher than that in the normal group. Obese group is significantly lower. Compared with obese cells, the significant reduction of the content of ROS in obesity-resistant cells can inhibit the production of apoptosis induced by high-fat diet oxidative stress, from the addition of the albinol can reduce the ROS content of the immune cells, relieve the oxidative stress, further reduce the apoptosis of the lymphocytes, chronic inflammatory response.3. Regulation of sugar metabolism by different treatment time of high-fat diet The effects of lymphocyte subpopulation on blood glucose, insulin and blood lipid increased significantly after 6 weeks of high-fat diet, the anti-oxidation ability decreased, the CD3 + CD4 +/ CD3 + CD8 + ratio and Tr in the spleen were decreased. The content of egs cells was significantly decreased, the content of Tregs in peripheral blood was significantly decreased, and body weight gain and spleen Tr were started at 13 weeks. After 6 weeks of high-fat diet, the expression of Nrf2 and PI3K in the spleen increased. At the beginning of 13 weeks, the expression of PI3K and AKT in the spleen significantly decreased, the expression of GSK-3 was significantly increased, the expression of anti-oxidation enzyme HO-1 was significantly decreased, and the expression of TNF-1 in the inflammatory cytokines increased significantly. After a week, the levels of insulin and blood lipid in the obesity-resistant group were significantly lower than that in the obese group, the anti-oxidation ability increased significantly, the CD3 + CD4 +/ CD3 + CD8 + ratio of the peripheral blood and the spleen and the ratio of the CD3 + CD4 +/ CD3 + CD8 + in the peripheral The content of Tregs increased. The expression of GLUT4 and SIRT1 of the glucose metabolism gene was increased by 13 weeks after the addition of the albinol, the blood sugar and insulin level of the high fat diet were decreased, the number of the lymphocyte subpopulations was increased, the expression of COX-2 and GSK-3 in the spleen was decreased, and the anti-oxidation enzyme gene expression of the spleen was increased after 26 weeks. to increase, to relieve the oxidative stress of the body, by increasing the number of lymphocytes, 4. Different treatment time of high-fat diet on T and B lymphocytes The effects of redox state and energy metabolism on the metabolism of high-fat diet for 3 weeks, T, B lymphocyte transformation were significantly reduced, and the total anti-oxidation ability of T-lymphocytes in the spleen was significant. elevated, T, B-lymphocytes Nrf2, antioxidant enzymes and PGC-1 The expression of Na-K-ATPase in B-lymphocytes increased significantly, and the expression of Na-K-ATPase in B-lymphocytes increased significantly. The anti-oxidation ability of B-lymphocytes was significantly decreased at 6 weeks, and the expression of T, B-lymphocytes Nrf2, anti-oxidation enzyme and SIRT1 decreased, and the expression of Na-K-ATPase and PGC-1 in T-cells was decreased. A significant decrease in mitochondrial membrane potential and a decrease in the level of ATP in the accelerated cells. The T, B lymphocyte transformation, anti-oxidation ability, line grain, There was no significant difference between the body membrane potential and the normal group. The expression of Nrf2 and its related anti-oxidation gene was significantly higher than that of the obese group. The expression of PGC-1 in T and B lymphocytes and the level of ATP in the normal group were increased significantly. The expression of SIRT1 in lymphocytes increased significantly. After 26 weeks of addition, the anti-oxidation gene expression of T and B lymphocytes increased, high-fat diet mediate oxidative stress to Tr There was a significant decrease in the expression of the related genes in the peripheral blood and spleen Tregs of the obese group and the content of ROS in the peripheral blood and spleen of the obese group. The expression of Nrf2 and its activated genes decreased, the expression of mitochondrial biosynthesis and function-related genes decreased, and the expression of Caspase3, DAPK1 and Bax increased. The expression of Bcl-2 decreased and the apoptosis rate of the cells increased. The expression of the related genes in the obesity-resistant Tregs was higher than that of the obese group, the expression of the anti-oxidation enzyme was significantly increased, and the ROS content was significantly decreased, so that the expression of the related genes related to the energy metabolism of the Tregs was increased, and the obesity-resistant group Tregs was fine. The expression and expression of apoptosis-related genes There was no significant difference in the normal group, and it was significantly decreased compared with the obese group. The addition of the albinol was enhanced by enhancing the anti-oxidation enzyme expression of the Tregs cell, removing the ROS in the cells, increasing the mitochondrial biosynthesis and function of the Tregs cell, increasing the energy metabolism of the cells, and slowing down. The functional damage of Tregs induced by high-fat diet can be induced. In conclusion, high-fat diet can induce excessive ROS production, damage the synthesis and function of the mitochondria, and the dysfunction of energy metabolism of the cell is the proportion of the lymphocyte subpopulation. An important factor in the regulation is to increase the chronic inflammatory response of the body. The obesity-resistant group can relieve the high-fat diet-mediated oxidation. The inhibition of energy metabolism in the cells and the ratio of lymphocyte subpopulations. The addition of the albinol is by removing excess ROS, relieving oxidative stress, and promoting the generation of mitochondrial energy.
【学位授予单位】：江南大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R151
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