小檗碱降糖调脂作用与PPARs/P-TEFb信号转导通路的关系
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摘要
2型糖尿病是由胰岛素抵抗和胰岛素分泌障碍导致的糖代谢紊乱疾病,常伴有高脂血症。过氧化物酶体增殖物激活受体(Peroxisome proliferators-activated receptors, PPARs)是依赖配体激活的核受体超家族成员之一,与配体结合后转录活性发生变化,导致PPARs靶基因表达的改变,从而引起脂肪细胞分化、脂质代谢等一系列生理活动。由周期素依赖性蛋白激酶9 (Cyclin-dependent kinase 9, CDK9)和细胞周期调节蛋白T1 (cyclin T1)组成的正性转录延伸因子b (Positive transcription elongation factor b, P-TEFb)可被一些转录因子招募以激活特异启动子的转录延伸,参与多种细胞的分化过程。PPARs在机体的糖脂代谢中起着重要作用,与糖尿病和高脂血症等的发生发展密切关系,临床上常用的胰岛素增敏型抗糖尿病药物罗格列酮就属于PPARγ激动剂,其中常用的降脂药物非诺贝特即为PPARα激动剂。单一的PPARγ激动剂药物存在体重增加、水肿和可能增加心血管事件等副作用,且无法改善脂代谢紊乱症状。中药单体成分小檗碱(Berberine)已有用于治疗糖尿病和高脂血症的实验和临床报道,但其确切机制尚未阐明。
目的
观察小檗碱对2型糖尿病大鼠血糖血脂和肝脏、骨骼肌中糖脂代谢,以及脂肪组织中PPARs和P-TEFb的mRNA和蛋白表达的影响。筛选最佳小干扰RNA (Small interference RNA, siRNA)序列,在最佳干扰浓度和时间下沉默CDK9 mRNA表达,3T3-L1细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA和蛋白的改变及小檗碱的干预作用。旨在探讨小檗碱对2型糖尿病的治疗作用及其改善糖脂代谢作用与PPARs/P-TEFb表达的关系,阐明小檗碱治疗糖尿病的作用机制。
方法
1. 2型糖尿病大鼠模型的建立:大鼠禁食12 h后用于建立2型糖尿病模型,根据文献及预实验确定链脲菌素(Streptozotocin, STZ)剂量为35 mg/kg,正常对照组大鼠腹腔注射等体积的柠檬酸缓冲液。标准饲料喂养2周,挑选空腹血糖值≥16.7 mmol/L的糖尿病大鼠改用高糖高脂饲料喂养14周以诱导高脂血症,正常对照组大鼠一直用标准饲料喂养。
2.实验分组及给药:于16周将空腹血糖值≥16.7 mmol/L的糖尿病大鼠按血糖值随机分为糖尿病模型组、小檗碱低、中、高剂量组(75、150、300 mg/kg)、非诺贝特组(100 mg/kg)和罗格列酮组(4 mg/kg) 6组,非诺贝特和罗格列酮作为阳性对照药。实验共分7组,其中正常对照组由同批次正常大鼠组成,每组10只动物。大鼠单笼饲养,每天拌食给药1次,连续给药16周,每4周测1次空腹血糖,每2周称1次体重,并根据体重调整给药剂量。
3. 2型糖尿病大鼠血糖、血脂、血清胰岛素等血液指标的检测:处死大鼠前禁食12 h,麻醉后心脏取血,每组5只大鼠用4%多聚甲醛灌注固定后取组织称重再固定,进行后续处理;另5只大鼠直接快速取组织称重后液氮冻存或固定后石蜡包埋。按相应方法进行血中血糖、甘油三酯(Triglyceride, TG)、总胆固醇(Total cholesterol, TC)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(Low density lipoprotein cholesterol, LDL-C)、载脂蛋白(Apolipoprotein, Apo)AI、ApoB、游离脂肪酸(Free fatty acid, FFA)、血清胰岛素、糖化血红蛋白(Hemoglobin A1c, HbA1c)、总脂酶、肿瘤坏死因子α(Tumor necrosis factor alpha, TNF-α)和脂联素等指标的检测。
4.观察胰岛普通、超微病理结构和胰岛素的表达:HE染色法观察胰岛的普通病理结构改变,运用透射电镜技术观察胰岛的超微病理结构变化。采用免疫组化技术检测胰岛内胰岛素的表达,使用相应试剂盒检测胰腺中的超氧化物歧化酶(Superoxide dismutase, SOD)活性和丙二醛(Malonaldehyde, MDA)含量。
5.肝脏和骨骼肌中糖脂代谢的检测:油红O染色法观察肝脏冰冻切片中脂质分布情况,过碘酸-希夫(氏)(PAS)染色法观察肝脏中糖原的分布情况。用糖原、FFA、TG检测试剂盒分别测定肝脏和骨骼肌中糖原、FFA、TG含量。
6.脂肪组织中PPARs、P-TEFb mRNA和蛋白表达等的测定:分别采用real time PCR和western blotting检测脂肪组织中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA和蛋白的表达。按相应方法检测脂肪组织中的TNF-α、脂联素、FFA、总脂酶、SOD和MDA等指标。采用HE染色观察脂肪组织细胞的大小和数量。
7. 3T3-L1脂肪细胞的增殖、分化和脂质集聚:培养3T3-L1脂肪细胞,运用MTT法和油红O染色法观察小檗碱对3T3-L1细胞增殖、脂肪细胞分化情况及采用western blotting检测脂肪细胞分化标记物aP2蛋白的表达。
8. 3T3-L1脂肪细胞中PPARs、P-TEFb表达的检测:3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA、蛋白表达、TNF-α、脂联素含量、细胞分化和细胞内脂质集聚的测定,以及在小檗碱、非诺贝特和罗格列酮作用下上述指标的变化。
9.最佳RNA干扰(RNAi)条件的确定:采用荧光标记的FAM-siRNA优化转染条件,运用real time PCR技术筛选最佳CDK9的siRNA序列,确定最有效siRNA沉默基因的最佳干扰浓度和时间,并观察siRNA转染后CDK9蛋白表达随时间的变化。
10. RNAi下3T3-L1脂肪细胞中PPARs、P-TEFb表达的检测:应用最有效siRNA序列的最佳干扰浓度转染,在沉默CDK9基因情况下,PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达、TNF-α、脂联素含量、细胞分化和细胞内脂质集聚的改变,以及在小檗碱、非诺贝特和罗格列酮作用下这些指标的变化。
结果
1. 2型糖尿病大鼠的空腹血糖、HbA1c较正常对照大鼠升高,TG、TC、LDL-C、ApoB和FFA与正常对照大鼠比较明显增高,HDL-C、ApoAI则降低,血清胰岛素较正常对照大鼠升高,表明成功建立了2型糖尿病大鼠模型。
2.小檗碱能明显降低2型糖尿病大鼠血糖和HbA1c水平,降低TG、TC、LDL-C、ApoB、FFA含量和增加HDL-C、ApoAI含量。小檗碱还可增加糖尿病大鼠肝脏和骨骼肌中糖原含量并降低FFA、TG含量。
3.小檗碱明显降低糖尿病大鼠血清胰岛素含量,提高胰岛素敏感指数和增加β细胞内胰岛素含量;增加胰腺重体重比值,HE染色显示小檗碱增加胰岛面积和β细胞数量,透射电镜结果表明小檗碱使胰岛β细胞中分泌颗粒数量上升,改善病变的超微结构;小檗碱增强胰腺中SOD活性和降低MDA含量。
4.小檗碱明显降低糖尿病大鼠血清和脂肪组织中FFA、MDA、TNF-α含量,增加脂联素含量,增强总脂酶和SOD活性,具有促进脂质代谢、抗氧化和调节脂肪因子分泌的功能。
5.小檗碱明显增强糖尿病大鼠脂肪组织中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白的表达,降低内脏脂肪重比重比值和脂肪细胞大小,增加脂肪细胞数量。
6.小檗碱在低浓度时促进3T3-L1细胞增殖和在高浓度时抑制其增殖,能浓度依赖性地促进脂肪细胞分化和降低脂质积聚。小檗碱可促进3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白的表达,抑制TNF-α分泌而增加脂联素分泌。
7. siRNAa为最佳沉默CDK9基因表达序列,最佳干扰浓度和时间分别为50 nmol/L和48 h。转染后48 h CDK9蛋白表达明显减弱,96 h恢复至正常水平。
8.在最有效siRNA序列最佳干扰浓度和时间条件下沉默CDK9基因表达,3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白表达均受到抑制,TNF-α分泌增加而脂联素分泌受到抑制。小檗碱对干扰效应具有翻转作用,能促进PPARs和P-TEFb表达,降低TNF-α分泌和促进脂联素分泌,促进细胞分化和降低脂质集聚。
结论
本研究一次性腹腔注射小剂量链脲菌素,造成部分胰岛β细胞破坏,使其发生糖尿病,接着采用高糖高脂饲料喂饲以诱发糖尿病大鼠的高脂血症。该模型不仅表现胰岛素抵抗,而且部分胰岛β细胞功能受损,糖脂代谢紊乱明显,与人类2型糖尿病病理机制相似,因此用来评价降糖调脂药物的疗效,结果可信。小檗碱对2型糖尿病大鼠具有明显的降糖调脂作用,除降低血糖、HbA1c水平和改善血脂代谢异常,还增加骨骼肌和肝糖原含量和降低脂质在肝脏、骨骼肌组织中的堆积。小檗碱能促进胰岛β细胞再生和增加β细胞内胰岛素含量。小檗碱通过调节糖脂代谢的平衡和恢复胰岛β细胞功能来改善胰岛素抵抗,引起血清胰岛素水平的降低。小檗碱通过使糖尿病大鼠脂肪组织中降低了的PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达恢复至接近正常大鼠水平,从而改善糖尿病大鼠的糖脂代谢。小檗碱能促进3T3-L1细胞分化和降低脂质积聚,其作用与通过促进3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达相关,与糖尿病大鼠实验结果相一致。RNAi下沉默CDK9基因,3T3-L1细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达受到抑制,小檗碱具有翻转并促进表达的作用。因此CDK9参与PPARs的表达调控,在PPARs与P-TEFb共同参与脂肪细胞分化和脂质集聚中有着重要作用,小檗碱可部分地通过影响CDK9参与脂肪细胞的分化功能,进而影响PPARs活性,使组织中糖脂代谢活动及相关酶、脂肪因子等恢复至接近常态,最终使2型糖尿病大鼠的糖脂代谢紊乱症状得以改善。因此,小檗碱的降糖调脂作用与其通过调控PPARs/P-TEFb信号转导通路相关,即小檗碱通过调控PPARs/P-TEFb信号转导通路是其降糖调脂作用的机制之一。
Type 2 diabetes mellitus is a metabolic disorder due to insulin resistance and insulin-secretion deficiency accompanying hyperlipidemia. Peroxisome proliferators-activated receptors (PPARs) are ligand dependent transcription factors that regulate expression of target genes related to lipid and glucose metabolism. The PPARs play critical roles in the regulation of the adipocyte differentiation and lipid metabolism. Cyclin-dependent kinase 9 (CDK9) and cyclin T1 are the two components of the positive transcription elongation factor b (P-TEFb). P-TEFb is required not only as a basic transcription elongation factor, but it is also recruited by some transcription factors to activate transcriptional elongation from specific promoters. P-TEFb involves in several specific differentiation processes of cells. Both PPARγagonists (rosiglitazone) and PPARαagonists (fenofibrate) have actions with distinct benefits for type 2 diabetes. Currently available pharmacological antidiabetic agents such as rosiglitazone, however, have various adverse effects and high rates of secondary failure. Experimental and clinical trials showed that berberine was a potential hypoglycemic drug to treat type 2 diabetic patients with dyslipidemia, but the mechanism still needs to investigate.
Objective
To investigate the effects of berberine on blood glucose, blood lipid, glucolipid metabolism in liver and skeletal muscle, and PPARs and P-TEFb mRNA and protein expression in adipose tissue of type 2 diabetic rats. To select optimal sequence of small interference RNA (siRNA) of CDK9 mRNA and the best interference concentration and action time of optimal siRNA, then to determine PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in 3T3-L1 cells and effect of berberine on them under this condition. To probe into beneficial effect of berberine on diabetic rats, relationship between hypoglycemic, hypolipidemic effects of berberine and PPARs/P-TEFb expression, and to illuminate the mechanism of antidiabetic effect of berberine.
Methods
1. To induce type 2 diabetic rats: Fasted rats were injected 35 mg/kg streptozotocin to induce diabetic rats according to literature and control rats were injected with the same volume citrate-phosphate buffer. After 2 weeks, the diabetic rats with fasting blood glucose level of above 16.7 mmol/L were given a high-carbohydrate/high-fat diet instead of a standard diet to induce hyperlipidemia and control rats were still given the standard diet.
2. Experimental group and drug treatment: The rats were divided into 7 groups, 10 animals in each group: age-matched control rats and diabetic rats without any drug treatment; diabetic rats treated with berberine at a dose of 75, 150 or 300 mg/kg every day, respectively; diabetic rats treated with fenofibrate at a dose of 100 mg/kg or rosiglitazone at a dose of 4 mg/kg every day, both served as positive control. The standard diet or the high-carbohydrate/high-fat diet was given only after drug, mixed with the standard diet, was completely ingested by the rats for 16 weeks. Animal weight was measured every 2 weeks throughout the experiment and the drug dose was accordingly adjusted. Fasting blood glucose levels were also detected at the end of week 20, 24, 28 (during treatment) and 32 (before sacrificed).
3. Measurement of blood index: Blood samples were collected from the heart after fasted rats were anaesthetized with an overdose of sodium pentobarbital at the end of week 32. Half of each group rats were perfused with 4% paraformaldehyde. Liver, pancreas and adipose tissue were excised and weighted, and fragments of the tissues were postfixed in 4% paraformaldehyde. Tissues of the other half animals were rapidly excised and weighed after blood collection. Part of tissues were cut into slices and frozen in liquid nitrogen for other studies. Another part of tissues was postfixed in 4% paraformaldehyde overnight for paraffin embedding. Total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), apolipoprotein (Apo) A?, ApoB, free fatty acid (FFA), serum insulin, hemoglobin A1c (HbA1c), total lipidase, tumor necrosis factor alpha (TNF-α) and adiponectin levels in blood were measured by commercial kit.
4. Investigation on histopathology, ultrastructure and insulin expression in pancreas: Hematoxylin-eosin (HE) staining and transmission electron microscope were used to observe pancreatic histopathology and ultrastructure ofβcells, respectively. Insulin expression in pancreas was measured by immunohistochemistry. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) level in pancreas were measured by commercial kit.
5. Measurement of glucolipid metabolism in liver and skeletal muscle: Oil red O staining and periodic acid-schiff (PAS) staining were used to observe lipid and glycogen distribution in liver, respectively. Glycogen, FFA and TG contents in liver and skeletal muscle were detected by commercial kit.
6. Determination of PPARs, P-TEFb mRNA and protein expression in adipose tissue: PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein were determined by real time PCR and western blotting. TNF-α, adiponectin, FFA, total lipidase, SOD and MDA in adipose tissue were measured by commercial kit. Hematoxylin-eosin staining was used to observe the size and number of adipocyte.
7. Proliferation, differentiation and lipid accumulation of 3T3-L1 cells: MTT assay and oil red O staining were used to detect proliferation and differentiation of 3T3-L1 cells, respectively. As a differentiation marker of adipocyte, aP2 protein was measured by western blotting.
8. Determination of PPARs and P-TEFb expression in 3T3-L1 adipocytes: Effects of berberine, fenofibrate and rosiglitazone on PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 mRNA and protein expression, TNF-αand adiponectin contents were measured in 3T3-L1 adipocytes.
9. Selection of optimal RNA interference (RNAi) condition: Fluorescently-labeled FAM-siRNA was used to optimize transfection condition; optimal siRNA sequence of CDK9, and the best interference concentration and action time of optimal siRNA were determined by real time PCR. CDK9 protein expression was analyzed at different time after optimal siRNA transfection.
10. Determination of PPARs and P-TEFb expression in 3T3-L1 adipocytes by RNAi: PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression, TNF-αand adiponectin contents were measured in 3T3-L1 adipocytes by RNAi. Effects of berberine, fenofibrate and rosiglitazone on them were observed.
Results
1. Fasting blood glucose, HbA1c, TG, TC, LDL-C, ApoB, FFA and serum insulin levels in diabetic rats were all significantly higher than that of the control ones, while HDL-C and ApoAI levels were significantly lower. These results indicated that type 2 diabetic rats with hyperlipidemia were successfully induced.
2. Berberine markedly decreased blood glucose, HbA1c, TG, TC, LDL-C, ApoB and FFA contents of type 2 diabetic rats, while increased HDL-C and ApoAI levels. Berberine increased the declined glycogen content in liver and skeletal muscle of diabetic rats, while decreased the augmented FFA and TG levels in diabetic tissues.
3. Berberine significantly decreased serum insulin content and insulin expression in pancreas of diabetic rats, increased insulin sensitivity index. Berberine augmented pancreas to body weight ratio, pancreatic islets area andβcells number. Berberine increased secretory granules, and improved the swollen mitochondrial and endoplasmic reticulum ofβcells in diabetic rats. Berberine increased SOD activity and decreased MDA content.
4. Berberine significantly declined FFA, MDA and TNF-αcontents in serum and adipose tissue of diabetic rats, while increased adiponectin level and total lipidase, SOD activities.
5. Berberine markedly up-regulated PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in adipose tissue of diabetic rats. Berberine decreased adipose tissue to body weight ratio and adipocyte size, and increased adipocyte number.
6. Berberine promoted 3T3-L1 cells proliferation at low concentration, but inhibited proliferation at high concentration. Berberine enhanced 3T3-L1 cells differentiation and degraded lipid accumulation in dose-dependent manner. Berberine up-regulated PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in 3T3-L1 adipocytes. Berberine inhibited TNF-αsecretion and increased adiponectin secretion.
7. siRNAa is the optimal siRNA sequence of CDK9, the best interference concentration and action time were 50 nmol/L and 48 h. CDK9 protein expression was significantly attenuated 48 h after transfection and restored to normal level 96 h after transfection.
8. PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression were all inhibited by RNAi in 3T3-L1 adipocytes, while TNF-αsecretion was augmented and adiponectin secretion was suppressed. Berberine turnovered the decreased PPARα, PPARδ, PPARγ, CDK9, cyclin T1 expression. Berberine inhibited TNF-αsecretion and increased adiponectin secretion.
Conclusions
Diabetic rats were developed by injection low dose streptozotocin due to parts ofβcells injury, and then hyperlipidemia was induced with the high-carbohydrate/high-fat diet. The diabetic rats showed insulin resistance and glucolipid metabolic disorder similar to those found in diabetic patients. It was confidently used to screen drugs with hypoglycemic and hypolipidemic effects. Berberine had significant hypoglycemic and hypolipidemic effects on diabetic rats, improved glucolipid metabolism in liver and skeletal muscle. Berberine promotedβcells regeneration and increased insulin content inβcells to preserveβcells function. Berberine decreased serum insulin due to improved metabolism and recoveredβcells function. Berberine restored the decreased PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 mRNA and protein expression in adipose tissue of diabetic rats to the control levels, which attributed to improved glucolipid metabolism. Berberine enhanced 3T3-L1 cells differentiation and decreased lipid accumulation, which may due to up-regulated PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 expression. When CDK9 mRNA expression was inhibited by RNAi, PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 expression were downregulated, which was turnovered and promoted by berberine. Berberine improved glucolipid metabolism both in blood and tissues of diabetic rats, promoted 3T3-L1 cells differentiation and inhibited lipid accumulation via modulating metabolic related PPARs expression and differentiation related P-TEFb expression, so regulation of PPARs/P-TEFb signal transduction pathway is one of the mechanisms of hypoglycemic, hypolipidemic effects of berberine.
目的
观察小檗碱对2型糖尿病大鼠血糖血脂和肝脏、骨骼肌中糖脂代谢,以及脂肪组织中PPARs和P-TEFb的mRNA和蛋白表达的影响。筛选最佳小干扰RNA (Small interference RNA, siRNA)序列,在最佳干扰浓度和时间下沉默CDK9 mRNA表达,3T3-L1细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA和蛋白的改变及小檗碱的干预作用。旨在探讨小檗碱对2型糖尿病的治疗作用及其改善糖脂代谢作用与PPARs/P-TEFb表达的关系,阐明小檗碱治疗糖尿病的作用机制。
方法
1. 2型糖尿病大鼠模型的建立:大鼠禁食12 h后用于建立2型糖尿病模型,根据文献及预实验确定链脲菌素(Streptozotocin, STZ)剂量为35 mg/kg,正常对照组大鼠腹腔注射等体积的柠檬酸缓冲液。标准饲料喂养2周,挑选空腹血糖值≥16.7 mmol/L的糖尿病大鼠改用高糖高脂饲料喂养14周以诱导高脂血症,正常对照组大鼠一直用标准饲料喂养。
2.实验分组及给药:于16周将空腹血糖值≥16.7 mmol/L的糖尿病大鼠按血糖值随机分为糖尿病模型组、小檗碱低、中、高剂量组(75、150、300 mg/kg)、非诺贝特组(100 mg/kg)和罗格列酮组(4 mg/kg) 6组,非诺贝特和罗格列酮作为阳性对照药。实验共分7组,其中正常对照组由同批次正常大鼠组成,每组10只动物。大鼠单笼饲养,每天拌食给药1次,连续给药16周,每4周测1次空腹血糖,每2周称1次体重,并根据体重调整给药剂量。
3. 2型糖尿病大鼠血糖、血脂、血清胰岛素等血液指标的检测:处死大鼠前禁食12 h,麻醉后心脏取血,每组5只大鼠用4%多聚甲醛灌注固定后取组织称重再固定,进行后续处理;另5只大鼠直接快速取组织称重后液氮冻存或固定后石蜡包埋。按相应方法进行血中血糖、甘油三酯(Triglyceride, TG)、总胆固醇(Total cholesterol, TC)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(Low density lipoprotein cholesterol, LDL-C)、载脂蛋白(Apolipoprotein, Apo)AI、ApoB、游离脂肪酸(Free fatty acid, FFA)、血清胰岛素、糖化血红蛋白(Hemoglobin A1c, HbA1c)、总脂酶、肿瘤坏死因子α(Tumor necrosis factor alpha, TNF-α)和脂联素等指标的检测。
4.观察胰岛普通、超微病理结构和胰岛素的表达:HE染色法观察胰岛的普通病理结构改变,运用透射电镜技术观察胰岛的超微病理结构变化。采用免疫组化技术检测胰岛内胰岛素的表达,使用相应试剂盒检测胰腺中的超氧化物歧化酶(Superoxide dismutase, SOD)活性和丙二醛(Malonaldehyde, MDA)含量。
5.肝脏和骨骼肌中糖脂代谢的检测:油红O染色法观察肝脏冰冻切片中脂质分布情况,过碘酸-希夫(氏)(PAS)染色法观察肝脏中糖原的分布情况。用糖原、FFA、TG检测试剂盒分别测定肝脏和骨骼肌中糖原、FFA、TG含量。
6.脂肪组织中PPARs、P-TEFb mRNA和蛋白表达等的测定:分别采用real time PCR和western blotting检测脂肪组织中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA和蛋白的表达。按相应方法检测脂肪组织中的TNF-α、脂联素、FFA、总脂酶、SOD和MDA等指标。采用HE染色观察脂肪组织细胞的大小和数量。
7. 3T3-L1脂肪细胞的增殖、分化和脂质集聚:培养3T3-L1脂肪细胞,运用MTT法和油红O染色法观察小檗碱对3T3-L1细胞增殖、脂肪细胞分化情况及采用western blotting检测脂肪细胞分化标记物aP2蛋白的表达。
8. 3T3-L1脂肪细胞中PPARs、P-TEFb表达的检测:3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1 mRNA、蛋白表达、TNF-α、脂联素含量、细胞分化和细胞内脂质集聚的测定,以及在小檗碱、非诺贝特和罗格列酮作用下上述指标的变化。
9.最佳RNA干扰(RNAi)条件的确定:采用荧光标记的FAM-siRNA优化转染条件,运用real time PCR技术筛选最佳CDK9的siRNA序列,确定最有效siRNA沉默基因的最佳干扰浓度和时间,并观察siRNA转染后CDK9蛋白表达随时间的变化。
10. RNAi下3T3-L1脂肪细胞中PPARs、P-TEFb表达的检测:应用最有效siRNA序列的最佳干扰浓度转染,在沉默CDK9基因情况下,PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达、TNF-α、脂联素含量、细胞分化和细胞内脂质集聚的改变,以及在小檗碱、非诺贝特和罗格列酮作用下这些指标的变化。
结果
1. 2型糖尿病大鼠的空腹血糖、HbA1c较正常对照大鼠升高,TG、TC、LDL-C、ApoB和FFA与正常对照大鼠比较明显增高,HDL-C、ApoAI则降低,血清胰岛素较正常对照大鼠升高,表明成功建立了2型糖尿病大鼠模型。
2.小檗碱能明显降低2型糖尿病大鼠血糖和HbA1c水平,降低TG、TC、LDL-C、ApoB、FFA含量和增加HDL-C、ApoAI含量。小檗碱还可增加糖尿病大鼠肝脏和骨骼肌中糖原含量并降低FFA、TG含量。
3.小檗碱明显降低糖尿病大鼠血清胰岛素含量,提高胰岛素敏感指数和增加β细胞内胰岛素含量;增加胰腺重体重比值,HE染色显示小檗碱增加胰岛面积和β细胞数量,透射电镜结果表明小檗碱使胰岛β细胞中分泌颗粒数量上升,改善病变的超微结构;小檗碱增强胰腺中SOD活性和降低MDA含量。
4.小檗碱明显降低糖尿病大鼠血清和脂肪组织中FFA、MDA、TNF-α含量,增加脂联素含量,增强总脂酶和SOD活性,具有促进脂质代谢、抗氧化和调节脂肪因子分泌的功能。
5.小檗碱明显增强糖尿病大鼠脂肪组织中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白的表达,降低内脏脂肪重比重比值和脂肪细胞大小,增加脂肪细胞数量。
6.小檗碱在低浓度时促进3T3-L1细胞增殖和在高浓度时抑制其增殖,能浓度依赖性地促进脂肪细胞分化和降低脂质积聚。小檗碱可促进3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白的表达,抑制TNF-α分泌而增加脂联素分泌。
7. siRNAa为最佳沉默CDK9基因表达序列,最佳干扰浓度和时间分别为50 nmol/L和48 h。转染后48 h CDK9蛋白表达明显减弱,96 h恢复至正常水平。
8.在最有效siRNA序列最佳干扰浓度和时间条件下沉默CDK9基因表达,3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9和cyclin T1 mRNA、蛋白表达均受到抑制,TNF-α分泌增加而脂联素分泌受到抑制。小檗碱对干扰效应具有翻转作用,能促进PPARs和P-TEFb表达,降低TNF-α分泌和促进脂联素分泌,促进细胞分化和降低脂质集聚。
结论
本研究一次性腹腔注射小剂量链脲菌素,造成部分胰岛β细胞破坏,使其发生糖尿病,接着采用高糖高脂饲料喂饲以诱发糖尿病大鼠的高脂血症。该模型不仅表现胰岛素抵抗,而且部分胰岛β细胞功能受损,糖脂代谢紊乱明显,与人类2型糖尿病病理机制相似,因此用来评价降糖调脂药物的疗效,结果可信。小檗碱对2型糖尿病大鼠具有明显的降糖调脂作用,除降低血糖、HbA1c水平和改善血脂代谢异常,还增加骨骼肌和肝糖原含量和降低脂质在肝脏、骨骼肌组织中的堆积。小檗碱能促进胰岛β细胞再生和增加β细胞内胰岛素含量。小檗碱通过调节糖脂代谢的平衡和恢复胰岛β细胞功能来改善胰岛素抵抗,引起血清胰岛素水平的降低。小檗碱通过使糖尿病大鼠脂肪组织中降低了的PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达恢复至接近正常大鼠水平,从而改善糖尿病大鼠的糖脂代谢。小檗碱能促进3T3-L1细胞分化和降低脂质积聚,其作用与通过促进3T3-L1脂肪细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达相关,与糖尿病大鼠实验结果相一致。RNAi下沉默CDK9基因,3T3-L1细胞中PPARα、PPARδ、PPARγ、CDK9、cyclin T1表达受到抑制,小檗碱具有翻转并促进表达的作用。因此CDK9参与PPARs的表达调控,在PPARs与P-TEFb共同参与脂肪细胞分化和脂质集聚中有着重要作用,小檗碱可部分地通过影响CDK9参与脂肪细胞的分化功能,进而影响PPARs活性,使组织中糖脂代谢活动及相关酶、脂肪因子等恢复至接近常态,最终使2型糖尿病大鼠的糖脂代谢紊乱症状得以改善。因此,小檗碱的降糖调脂作用与其通过调控PPARs/P-TEFb信号转导通路相关,即小檗碱通过调控PPARs/P-TEFb信号转导通路是其降糖调脂作用的机制之一。
Type 2 diabetes mellitus is a metabolic disorder due to insulin resistance and insulin-secretion deficiency accompanying hyperlipidemia. Peroxisome proliferators-activated receptors (PPARs) are ligand dependent transcription factors that regulate expression of target genes related to lipid and glucose metabolism. The PPARs play critical roles in the regulation of the adipocyte differentiation and lipid metabolism. Cyclin-dependent kinase 9 (CDK9) and cyclin T1 are the two components of the positive transcription elongation factor b (P-TEFb). P-TEFb is required not only as a basic transcription elongation factor, but it is also recruited by some transcription factors to activate transcriptional elongation from specific promoters. P-TEFb involves in several specific differentiation processes of cells. Both PPARγagonists (rosiglitazone) and PPARαagonists (fenofibrate) have actions with distinct benefits for type 2 diabetes. Currently available pharmacological antidiabetic agents such as rosiglitazone, however, have various adverse effects and high rates of secondary failure. Experimental and clinical trials showed that berberine was a potential hypoglycemic drug to treat type 2 diabetic patients with dyslipidemia, but the mechanism still needs to investigate.
Objective
To investigate the effects of berberine on blood glucose, blood lipid, glucolipid metabolism in liver and skeletal muscle, and PPARs and P-TEFb mRNA and protein expression in adipose tissue of type 2 diabetic rats. To select optimal sequence of small interference RNA (siRNA) of CDK9 mRNA and the best interference concentration and action time of optimal siRNA, then to determine PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in 3T3-L1 cells and effect of berberine on them under this condition. To probe into beneficial effect of berberine on diabetic rats, relationship between hypoglycemic, hypolipidemic effects of berberine and PPARs/P-TEFb expression, and to illuminate the mechanism of antidiabetic effect of berberine.
Methods
1. To induce type 2 diabetic rats: Fasted rats were injected 35 mg/kg streptozotocin to induce diabetic rats according to literature and control rats were injected with the same volume citrate-phosphate buffer. After 2 weeks, the diabetic rats with fasting blood glucose level of above 16.7 mmol/L were given a high-carbohydrate/high-fat diet instead of a standard diet to induce hyperlipidemia and control rats were still given the standard diet.
2. Experimental group and drug treatment: The rats were divided into 7 groups, 10 animals in each group: age-matched control rats and diabetic rats without any drug treatment; diabetic rats treated with berberine at a dose of 75, 150 or 300 mg/kg every day, respectively; diabetic rats treated with fenofibrate at a dose of 100 mg/kg or rosiglitazone at a dose of 4 mg/kg every day, both served as positive control. The standard diet or the high-carbohydrate/high-fat diet was given only after drug, mixed with the standard diet, was completely ingested by the rats for 16 weeks. Animal weight was measured every 2 weeks throughout the experiment and the drug dose was accordingly adjusted. Fasting blood glucose levels were also detected at the end of week 20, 24, 28 (during treatment) and 32 (before sacrificed).
3. Measurement of blood index: Blood samples were collected from the heart after fasted rats were anaesthetized with an overdose of sodium pentobarbital at the end of week 32. Half of each group rats were perfused with 4% paraformaldehyde. Liver, pancreas and adipose tissue were excised and weighted, and fragments of the tissues were postfixed in 4% paraformaldehyde. Tissues of the other half animals were rapidly excised and weighed after blood collection. Part of tissues were cut into slices and frozen in liquid nitrogen for other studies. Another part of tissues was postfixed in 4% paraformaldehyde overnight for paraffin embedding. Total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), apolipoprotein (Apo) A?, ApoB, free fatty acid (FFA), serum insulin, hemoglobin A1c (HbA1c), total lipidase, tumor necrosis factor alpha (TNF-α) and adiponectin levels in blood were measured by commercial kit.
4. Investigation on histopathology, ultrastructure and insulin expression in pancreas: Hematoxylin-eosin (HE) staining and transmission electron microscope were used to observe pancreatic histopathology and ultrastructure ofβcells, respectively. Insulin expression in pancreas was measured by immunohistochemistry. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) level in pancreas were measured by commercial kit.
5. Measurement of glucolipid metabolism in liver and skeletal muscle: Oil red O staining and periodic acid-schiff (PAS) staining were used to observe lipid and glycogen distribution in liver, respectively. Glycogen, FFA and TG contents in liver and skeletal muscle were detected by commercial kit.
6. Determination of PPARs, P-TEFb mRNA and protein expression in adipose tissue: PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein were determined by real time PCR and western blotting. TNF-α, adiponectin, FFA, total lipidase, SOD and MDA in adipose tissue were measured by commercial kit. Hematoxylin-eosin staining was used to observe the size and number of adipocyte.
7. Proliferation, differentiation and lipid accumulation of 3T3-L1 cells: MTT assay and oil red O staining were used to detect proliferation and differentiation of 3T3-L1 cells, respectively. As a differentiation marker of adipocyte, aP2 protein was measured by western blotting.
8. Determination of PPARs and P-TEFb expression in 3T3-L1 adipocytes: Effects of berberine, fenofibrate and rosiglitazone on PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 mRNA and protein expression, TNF-αand adiponectin contents were measured in 3T3-L1 adipocytes.
9. Selection of optimal RNA interference (RNAi) condition: Fluorescently-labeled FAM-siRNA was used to optimize transfection condition; optimal siRNA sequence of CDK9, and the best interference concentration and action time of optimal siRNA were determined by real time PCR. CDK9 protein expression was analyzed at different time after optimal siRNA transfection.
10. Determination of PPARs and P-TEFb expression in 3T3-L1 adipocytes by RNAi: PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression, TNF-αand adiponectin contents were measured in 3T3-L1 adipocytes by RNAi. Effects of berberine, fenofibrate and rosiglitazone on them were observed.
Results
1. Fasting blood glucose, HbA1c, TG, TC, LDL-C, ApoB, FFA and serum insulin levels in diabetic rats were all significantly higher than that of the control ones, while HDL-C and ApoAI levels were significantly lower. These results indicated that type 2 diabetic rats with hyperlipidemia were successfully induced.
2. Berberine markedly decreased blood glucose, HbA1c, TG, TC, LDL-C, ApoB and FFA contents of type 2 diabetic rats, while increased HDL-C and ApoAI levels. Berberine increased the declined glycogen content in liver and skeletal muscle of diabetic rats, while decreased the augmented FFA and TG levels in diabetic tissues.
3. Berberine significantly decreased serum insulin content and insulin expression in pancreas of diabetic rats, increased insulin sensitivity index. Berberine augmented pancreas to body weight ratio, pancreatic islets area andβcells number. Berberine increased secretory granules, and improved the swollen mitochondrial and endoplasmic reticulum ofβcells in diabetic rats. Berberine increased SOD activity and decreased MDA content.
4. Berberine significantly declined FFA, MDA and TNF-αcontents in serum and adipose tissue of diabetic rats, while increased adiponectin level and total lipidase, SOD activities.
5. Berberine markedly up-regulated PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in adipose tissue of diabetic rats. Berberine decreased adipose tissue to body weight ratio and adipocyte size, and increased adipocyte number.
6. Berberine promoted 3T3-L1 cells proliferation at low concentration, but inhibited proliferation at high concentration. Berberine enhanced 3T3-L1 cells differentiation and degraded lipid accumulation in dose-dependent manner. Berberine up-regulated PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression in 3T3-L1 adipocytes. Berberine inhibited TNF-αsecretion and increased adiponectin secretion.
7. siRNAa is the optimal siRNA sequence of CDK9, the best interference concentration and action time were 50 nmol/L and 48 h. CDK9 protein expression was significantly attenuated 48 h after transfection and restored to normal level 96 h after transfection.
8. PPARα, PPARδ, PPARγ, CDK9, cyclin T1 mRNA and protein expression were all inhibited by RNAi in 3T3-L1 adipocytes, while TNF-αsecretion was augmented and adiponectin secretion was suppressed. Berberine turnovered the decreased PPARα, PPARδ, PPARγ, CDK9, cyclin T1 expression. Berberine inhibited TNF-αsecretion and increased adiponectin secretion.
Conclusions
Diabetic rats were developed by injection low dose streptozotocin due to parts ofβcells injury, and then hyperlipidemia was induced with the high-carbohydrate/high-fat diet. The diabetic rats showed insulin resistance and glucolipid metabolic disorder similar to those found in diabetic patients. It was confidently used to screen drugs with hypoglycemic and hypolipidemic effects. Berberine had significant hypoglycemic and hypolipidemic effects on diabetic rats, improved glucolipid metabolism in liver and skeletal muscle. Berberine promotedβcells regeneration and increased insulin content inβcells to preserveβcells function. Berberine decreased serum insulin due to improved metabolism and recoveredβcells function. Berberine restored the decreased PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 mRNA and protein expression in adipose tissue of diabetic rats to the control levels, which attributed to improved glucolipid metabolism. Berberine enhanced 3T3-L1 cells differentiation and decreased lipid accumulation, which may due to up-regulated PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 expression. When CDK9 mRNA expression was inhibited by RNAi, PPARα, PPARδ, PPARγ, CDK9, and cyclin T1 expression were downregulated, which was turnovered and promoted by berberine. Berberine improved glucolipid metabolism both in blood and tissues of diabetic rats, promoted 3T3-L1 cells differentiation and inhibited lipid accumulation via modulating metabolic related PPARs expression and differentiation related P-TEFb expression, so regulation of PPARs/P-TEFb signal transduction pathway is one of the mechanisms of hypoglycemic, hypolipidemic effects of berberine.
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