不同脂肪酸饮食对大鼠胰岛β细胞功能的影响及其机制的探讨
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摘要
目的:本文拟通过分析不同脂肪酸饮食喂养的大鼠胰岛细胞功能和胰岛细胞内真核生物翻译起始因子2的α亚基(p-eIF2α)、RNA依赖的蛋白激酶样激酶(p-PERK)和CCAAT/增强子结合蛋白(C/EBP)同源蛋白(CHOP)的表达,探索不同种类脂肪酸对胰岛β细胞功能及胰岛细胞内质网应激的影响。
方法:体重250~300g的雄性Wistar大鼠40只,随机分配到四个饮食组,即正常对照组和三个高脂组。正常对照组(N)给予基础饲料,热量组成:碳水化合物65.5%,脂肪10.3%,蛋白质24.2%,总热量为348kcal/100g。三个高脂组分别为:高单不饱和脂肪酸组(M)、高多不饱和脂肪酸组(P)、高饱和脂肪酸组(S),其热量组成均为碳水化合物47.2%,脂肪35.4 %,蛋白质17.4%,总热量为501kcal/100g,其中M组脂肪酸由茶油提供,P组脂肪酸由豆油提供,S组脂肪酸由猪油提供。干预8周后,称体重,行静脉糖耐量试验(IVGTT),公式计算第一时相胰岛素分泌AIR=(Ins1’+Ins3’+Ins5’+Ins8’) /4–FINS(空腹胰岛素)。实验后立即取材,留取血清测定甘油三酯(TG),血清总胆固醇(TC)和游离脂肪酸(FFA)的含量,留取胰腺样本用于免疫组化染色及分子生物学检查。
结果:1.饮食干预8周后,四组大鼠体重均明显增加,但组间没有统计学差异(P >0.05)。2. 8周时,S组FBG(空腹血糖)、FINS、TG、TC及FFA较N组均有明显升高,差异有统计学意义(P <0.05)。P组仅FBG及FINS较N组升高,差异有统计学意义(P <0.05)。M组上述指标较N组均无统计学差异(P >0.05)。3.静脉糖耐量试验结果,高脂饮食各组大鼠静脉推注葡萄糖后各点血糖值(BG)较N组均有所升高,其中S组1分钟、5分钟血糖值升高最明显,差异有统计学意义(P <0.01),余各点血糖值与N组比较无统计学差异。P组与M组推糖后各点血糖较N组均无差异。另外,高脂组大鼠静脉推糖后胰岛素值较N组有明显变化,S组推糖后各点胰岛素值(INS)较N组均明显降低,差异有统计学意义(P <0.05),P组第1、3、5分钟胰岛素较N组降低,差异有统计学意义(P<0.05),M组大鼠推糖后第5分钟胰岛素较N组有统计学差异(P <0.05)。三组高脂组大鼠AIR与N组均有统计学差异。4.免疫组化结果,三组高脂组p-PERK及p-eIFα的表达量较N组均有所增加,但只有S组(P <0.01)和P组(P <0.05)与N组有统计学差异。5.蛋白表达结果,三组高脂组胰腺细胞内p-eIF2α及CHOP的表达较N组均有所增加,其中S组(P <0.01)和P组(P <0.05)与N组有统计学差异,M组与N组无统计学差异。6.相关分析,AIR分别与p-PERK、p-eIF2α、CHOP、FBG及FINS的表达呈负相关(相关系数分别是r=-0.890 P <0.01; r=-0.656 P <0.01; r=-0.772 P <0.01; r=-0.606 P <0.05; r=-0.865 P <0.01)。CHOP的表达与p-PERK(r=0.771,P<0.01)、p-eIF2α(r=0.587,P<0.05)呈正相关,p-eIF2α的表达与p-PERK呈正相关(r=0.707,P<0.01)。
结论:
1.高脂饮食可以使大鼠血清总胆固醇、甘油三酯、游离脂肪酸、空腹血糖、空腹血清胰岛素不同程度升高,并对大鼠胰岛β细胞的分泌功能造成损伤,其中,高饱和脂肪酸饮食组大鼠胰岛β细胞功能受损最严重。
2.高脂饮食可诱导胰岛细胞内p-PERK及p-eIF2α的表达增加,并上调凋亡信号分子CHOP。其中,高饱和脂肪酸此诱导效应最强,可以充分诱导内质网应激的发生,依次为高多不饱和脂肪酸及高单不饱和脂肪酸。3.高脂饮食可能通过诱发胰岛细胞内质网应激、激活凋亡信号通路,而损伤β细胞的分泌功能。
Objective: We aim to investigate the effects of dietary fat on the function and endoplasmic reticulum stress of pancreatic beta cells by performing the intravenous glucose tolerance test (IVGTT) and detecting the changes in expression of p-PERK [PKR (double stranded RNA-dependent protein kinase)-like endoplasmic reticulum kinase], p-eIF2α(α-subunit of eukaryotic translational initiation factor 2) and CHOP [C/EBP (CCAAT ? enhancer-binding protein) homologous protein] in pancreatic cells.
Methods: Forty male Wistar rats (250~300g) were randomly divided into four groups: a control group and three groups fed with different high fat diet. The control group (N, n=10) was fed with a regular low fatty acids diet containing 10.3% fat, 24.2% protein, and 65.5% carbohydrate as percentage of total calories. Three high fat diet groups include high monounsaturated fatty acids diet group (M, n=10), high polyunsaturated fatty acids diet group (P, n=10) and high saturated fatty acids diet group (S, n=10), which contain 35.4% fat, 17.4% protein and 47.2% carbohydrate as a percentage of total calories. The fatty acids component of M group, P group and S group were from tea oil, soybean oil and lard oil respectively. At the end of 8-weeks feeding, the body weight of each individual rat was recorded, intravenous glucose tolerance test (IVGTT) was performed and acute insulin response (AIR) [AIR=(Ins1’+Ins3’+Ins5’+Ins8’)/4–FINS (fasting insulin)] was calculated. Blood samples were collected and the serum were then separated for the determination of blood lipids. Pancreas was collected for detecting p-eIF2αand p-PERK by immunohistochemisty and for p-eIF2αand CHOP by western-blot.
Results: 1. After 8 weeks of diet intervention, the body weight in all high fat groups increased, but there were no statistical differences among the four groups (P >0.05). 2. At the end of 8-weeks feeding, fasting blood glucose(FBG), FINS, serum total cholesterol(TC), triglyceride(TG) and free fatty acids (FFA) of S group increased significantly compared with N group (P <0.05). The FBG and FINS of P group were significantly higher than those of N group (P <0.05). 3. BG at every time point after glucose bolus was higher than that of N group. BG at 1 min and 5 min of S group increased significantly compared with N group (P <0.01), The BG at other time points showed no significant difference from N group. There was no significant difference in BG among M group, P group and N group. INS concentration at all time points of S group decreased significantly compared with N group (P <0.05). INS concentration at 1min, 3 min and 5 min in P group and at 5min in M group after glucose bolus were statistically lower than those in N group (P <0.05). There was no statistical difference among the others. The AIRs of three high fat groups were significantly lower than that in N group. 4. Immunohistochemisty analysis showed that the expression of p-PERK and p-eIF2αin S group (P <0.01) and P group (P <0.05) increased significantly than that of N group, but there was no difference between M group and N group (P >0.05). 5. Western blot analysis showed that the protein expression of p-eIF2αand CHOP of all high fat groups increased. Among the three groups, protein levels of p-eIF2αof S group and P group were significantly higher than that of N group (P =0.014, P =0.022 respectively), and so was CHOP (P =0.007, P =0.046 respectively). However, there was no significant difference between M group and N group (P >0.05). 6. AIR was negatively correlated with p-PERK, p-eIF2αand CHOP protein expression, FBG and FINS (r=-0.890 P <0.01; r=-0.656 P <0.01; r=-0.772 P <0.01; r=-0.606 P <0.05; r=-0.865 P <0.01, respectively). CHOP protein expression was highly positively correlated with the protein levels of p-PERK, p-eIF2α(r=0.771 P <0.01; r=0.587 P <0.05, respectively). And the protein levels of p-eIF2αwas in high positive correlation with p-PERK (r=0.771 P <0.01).
Conclusions: 1. The total cholesterol, triglyceride, FFAs, FBG and FINS of high fat groups increased whileβcell function decreased compared with N group. Intravenous glucose tolerance test demonstrated impaired function ofβcells in three high fat groups, of which the high saturated fatty acids diet group displayed most severe impairment. 2. High fat diets induce higher expression of p-PERK, p-eIF2αand downstream component apoptosis factor CHOP compared with normal diet. Among the three high fat diets, high saturated fatty acids diet has the most potent effect on the change of ER stress markers, and polyunsaturated fatty acids and monounsaturated fatty acids in turns. 3. High fat diets appear to impairβcell function by inducing ER stress and apoptosis.
方法:体重250~300g的雄性Wistar大鼠40只,随机分配到四个饮食组,即正常对照组和三个高脂组。正常对照组(N)给予基础饲料,热量组成:碳水化合物65.5%,脂肪10.3%,蛋白质24.2%,总热量为348kcal/100g。三个高脂组分别为:高单不饱和脂肪酸组(M)、高多不饱和脂肪酸组(P)、高饱和脂肪酸组(S),其热量组成均为碳水化合物47.2%,脂肪35.4 %,蛋白质17.4%,总热量为501kcal/100g,其中M组脂肪酸由茶油提供,P组脂肪酸由豆油提供,S组脂肪酸由猪油提供。干预8周后,称体重,行静脉糖耐量试验(IVGTT),公式计算第一时相胰岛素分泌AIR=(Ins1’+Ins3’+Ins5’+Ins8’) /4–FINS(空腹胰岛素)。实验后立即取材,留取血清测定甘油三酯(TG),血清总胆固醇(TC)和游离脂肪酸(FFA)的含量,留取胰腺样本用于免疫组化染色及分子生物学检查。
结果:1.饮食干预8周后,四组大鼠体重均明显增加,但组间没有统计学差异(P >0.05)。2. 8周时,S组FBG(空腹血糖)、FINS、TG、TC及FFA较N组均有明显升高,差异有统计学意义(P <0.05)。P组仅FBG及FINS较N组升高,差异有统计学意义(P <0.05)。M组上述指标较N组均无统计学差异(P >0.05)。3.静脉糖耐量试验结果,高脂饮食各组大鼠静脉推注葡萄糖后各点血糖值(BG)较N组均有所升高,其中S组1分钟、5分钟血糖值升高最明显,差异有统计学意义(P <0.01),余各点血糖值与N组比较无统计学差异。P组与M组推糖后各点血糖较N组均无差异。另外,高脂组大鼠静脉推糖后胰岛素值较N组有明显变化,S组推糖后各点胰岛素值(INS)较N组均明显降低,差异有统计学意义(P <0.05),P组第1、3、5分钟胰岛素较N组降低,差异有统计学意义(P<0.05),M组大鼠推糖后第5分钟胰岛素较N组有统计学差异(P <0.05)。三组高脂组大鼠AIR与N组均有统计学差异。4.免疫组化结果,三组高脂组p-PERK及p-eIFα的表达量较N组均有所增加,但只有S组(P <0.01)和P组(P <0.05)与N组有统计学差异。5.蛋白表达结果,三组高脂组胰腺细胞内p-eIF2α及CHOP的表达较N组均有所增加,其中S组(P <0.01)和P组(P <0.05)与N组有统计学差异,M组与N组无统计学差异。6.相关分析,AIR分别与p-PERK、p-eIF2α、CHOP、FBG及FINS的表达呈负相关(相关系数分别是r=-0.890 P <0.01; r=-0.656 P <0.01; r=-0.772 P <0.01; r=-0.606 P <0.05; r=-0.865 P <0.01)。CHOP的表达与p-PERK(r=0.771,P<0.01)、p-eIF2α(r=0.587,P<0.05)呈正相关,p-eIF2α的表达与p-PERK呈正相关(r=0.707,P<0.01)。
结论:
1.高脂饮食可以使大鼠血清总胆固醇、甘油三酯、游离脂肪酸、空腹血糖、空腹血清胰岛素不同程度升高,并对大鼠胰岛β细胞的分泌功能造成损伤,其中,高饱和脂肪酸饮食组大鼠胰岛β细胞功能受损最严重。
2.高脂饮食可诱导胰岛细胞内p-PERK及p-eIF2α的表达增加,并上调凋亡信号分子CHOP。其中,高饱和脂肪酸此诱导效应最强,可以充分诱导内质网应激的发生,依次为高多不饱和脂肪酸及高单不饱和脂肪酸。3.高脂饮食可能通过诱发胰岛细胞内质网应激、激活凋亡信号通路,而损伤β细胞的分泌功能。
Objective: We aim to investigate the effects of dietary fat on the function and endoplasmic reticulum stress of pancreatic beta cells by performing the intravenous glucose tolerance test (IVGTT) and detecting the changes in expression of p-PERK [PKR (double stranded RNA-dependent protein kinase)-like endoplasmic reticulum kinase], p-eIF2α(α-subunit of eukaryotic translational initiation factor 2) and CHOP [C/EBP (CCAAT ? enhancer-binding protein) homologous protein] in pancreatic cells.
Methods: Forty male Wistar rats (250~300g) were randomly divided into four groups: a control group and three groups fed with different high fat diet. The control group (N, n=10) was fed with a regular low fatty acids diet containing 10.3% fat, 24.2% protein, and 65.5% carbohydrate as percentage of total calories. Three high fat diet groups include high monounsaturated fatty acids diet group (M, n=10), high polyunsaturated fatty acids diet group (P, n=10) and high saturated fatty acids diet group (S, n=10), which contain 35.4% fat, 17.4% protein and 47.2% carbohydrate as a percentage of total calories. The fatty acids component of M group, P group and S group were from tea oil, soybean oil and lard oil respectively. At the end of 8-weeks feeding, the body weight of each individual rat was recorded, intravenous glucose tolerance test (IVGTT) was performed and acute insulin response (AIR) [AIR=(Ins1’+Ins3’+Ins5’+Ins8’)/4–FINS (fasting insulin)] was calculated. Blood samples were collected and the serum were then separated for the determination of blood lipids. Pancreas was collected for detecting p-eIF2αand p-PERK by immunohistochemisty and for p-eIF2αand CHOP by western-blot.
Results: 1. After 8 weeks of diet intervention, the body weight in all high fat groups increased, but there were no statistical differences among the four groups (P >0.05). 2. At the end of 8-weeks feeding, fasting blood glucose(FBG), FINS, serum total cholesterol(TC), triglyceride(TG) and free fatty acids (FFA) of S group increased significantly compared with N group (P <0.05). The FBG and FINS of P group were significantly higher than those of N group (P <0.05). 3. BG at every time point after glucose bolus was higher than that of N group. BG at 1 min and 5 min of S group increased significantly compared with N group (P <0.01), The BG at other time points showed no significant difference from N group. There was no significant difference in BG among M group, P group and N group. INS concentration at all time points of S group decreased significantly compared with N group (P <0.05). INS concentration at 1min, 3 min and 5 min in P group and at 5min in M group after glucose bolus were statistically lower than those in N group (P <0.05). There was no statistical difference among the others. The AIRs of three high fat groups were significantly lower than that in N group. 4. Immunohistochemisty analysis showed that the expression of p-PERK and p-eIF2αin S group (P <0.01) and P group (P <0.05) increased significantly than that of N group, but there was no difference between M group and N group (P >0.05). 5. Western blot analysis showed that the protein expression of p-eIF2αand CHOP of all high fat groups increased. Among the three groups, protein levels of p-eIF2αof S group and P group were significantly higher than that of N group (P =0.014, P =0.022 respectively), and so was CHOP (P =0.007, P =0.046 respectively). However, there was no significant difference between M group and N group (P >0.05). 6. AIR was negatively correlated with p-PERK, p-eIF2αand CHOP protein expression, FBG and FINS (r=-0.890 P <0.01; r=-0.656 P <0.01; r=-0.772 P <0.01; r=-0.606 P <0.05; r=-0.865 P <0.01, respectively). CHOP protein expression was highly positively correlated with the protein levels of p-PERK, p-eIF2α(r=0.771 P <0.01; r=0.587 P <0.05, respectively). And the protein levels of p-eIF2αwas in high positive correlation with p-PERK (r=0.771 P <0.01).
Conclusions: 1. The total cholesterol, triglyceride, FFAs, FBG and FINS of high fat groups increased whileβcell function decreased compared with N group. Intravenous glucose tolerance test demonstrated impaired function ofβcells in three high fat groups, of which the high saturated fatty acids diet group displayed most severe impairment. 2. High fat diets induce higher expression of p-PERK, p-eIF2αand downstream component apoptosis factor CHOP compared with normal diet. Among the three high fat diets, high saturated fatty acids diet has the most potent effect on the change of ER stress markers, and polyunsaturated fatty acids and monounsaturated fatty acids in turns. 3. High fat diets appear to impairβcell function by inducing ER stress and apoptosis.
引文
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1 1 Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmicreticulum stress. Cell Death and Differentiation, 2004, 11: 381–389
2 Hiderou Y. ER stress and diseases. FEBS Journal , 2007, 274:630–658
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4 Gordon PM, Anna AZ, Richard SJ. HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation. Cellular Signalling, 2008, 20: 347–358
5 Miriam C, Mariana IE, Daniel AC. An update on lipotoxic endoplasmic reticulum stress in pancreaticβ-cells. Biochem. Soc. Trans, 2008, 36:909–915
6 Herbach N, Rathkolb B, Kemter E et al. Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severeβ-cell loss in Munich Ins2C95S mutant mice. Diabetes, 2007, 56: 1268–1276
7 Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat. Rev. Genet, 2007, 8:657–662
8 Huang CJ, Lin CY, Haataja L, et al. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediatedβ-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes, 2007, 56: 2016–2027
9 Laybutt RD, Preston AM, Akerfeldt MC, et al. Endoplasmic reticulum stress contributes toβ-cell apoptosis in type 2 diabetes. Diabetologia, 2007, 50:752–763
10 Marchetti P, Bugliani M, Lupi,R, et al. The endoplasmic reticulum in pancreaticβ-cells of type 2 diabetes patients. Diabetologia, 2007, 50: 2486–2494
11 Fonseca SG, Lipson KL, Urano F et al. Endoplasmic Reticulum Stress Signaling in PancreaticβCells. Antioxid Redox Signal, 2007, 9(12):2335-2344.
12 Cardozo AK, Ortis F, Storling J, et al. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and depleteendoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta cells. Diabetes, 2005, 54: 452–461.
13 Hartman MG, Lu D, Kim ML et al. Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol Cell Biol, 2004 ,24: 5721–5732
14 Lipson KL, Fonseca SG, Ishigaki S, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab, 2006, 4: 245–254.
15 Pierre P, Fernanda Os, Miriam C, et al. Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells. DIABETES, 2007, 56:1069-1077
16 Srinivasan S, Ohsugi M, Liu Z, et al . Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells. Diabetes, 2005, 54: 968–975
17 Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem, 2005, 280: 847–851
18 Yusta B, Baggio LL, Estall JL et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab, 2006, 4: 391–406