JAK2/STAT3通路对小鼠生脂和脂解基因转录的影响
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摘要
JAK/STATs途径是多种细胞生长、存活、凋亡、应激及分化功能发挥过程中重要的细胞内信号传导途径。脂肪作为能量代谢的重要组织,在能量代谢中发挥重要的作用,一旦脂代谢发生紊乱,机体将会出现一系列病理变化。脂肪酸合成酶(FAS)是脂类生成的关键酶,过氧化物酶增殖体活化受体(PPARγ)是脂代谢中重要的转录因子,激素敏感脂酶(HSL)是脂肪分解的限速酶,瘦素(Leptin)在能量平衡中起重要作用。本试验以小鼠为研究对象,研究AG490和盐酸罗格列酮对小鼠脂肪组织和肝脏中脂代谢相关基因FAS、PPARγ、Leptin和HSL转录表达的影响,探讨JAK2/STAT3通路对脂肪生成及分解的作用。主要研究结果如下:
1.饲喂普通日粮下,AG490处理组小鼠体重显著降低,附睾脂肪沉积减少,血脂指标中HDL-C含量降低,脂肪酶活性升高。在脂肪组织中,JAK2和STAT3基因转录水平显著下调,同时FAS和Leptin基因转录水平显著降低,但PPARγ和HSL基因表达无显著变化;肝脏中JAK2和STAT3基因转录也明显下调。
盐酸罗格列酮处理组小鼠肝脏脂肪酶活性显著升高,而体重、附睾脂肪含量、血脂指标均无明显变化;在脂肪组织中,JAK2和STAT3基因转录无变化,而FAS转录显著降低,PPARγ基因转录极显著升高,Leptin和HSL基因表达无变化;肝脏中仅PPARγ基因表达量上升,FAS、Leptin和HSL基因表达量无变化。
2.高脂日粮饲喂下,AG490处理组小鼠体重在第7天开始显著下降,到第14天依然保持显著状态,附睾脂肪、血脂指标均显著低于对照组;脂肪组织中JAK2、STAT3和HSL mRNA表达量显著降低,FAS mRNA表达量极显著降低,PPARγ和Leptin mRNA表达量无变化;肝脏中JAK2/STAT3通路基因mRNA表达变化同脂肪组织一致,PPARγ和HSL mRNA表达量显著降低,FAS和Leptin mRNA表达量无变化。
盐酸罗格列酮处理组肝脏脂肪酶显著升高;脂肪组织和肝脏中JAK2 mRNA表达量均显著降低,脂肪组织中FAS和HSL mRNA表达量显著降低,PPARγmRNA表达量显著增高,Leptin mRNA表达量无变化;肝脏中仅FAS mRNA表达量显著降低外,其它基因无变化。
3.肥胖模型小鼠在普通日粮饲喂情况下,AG490处理组小鼠体重、附睾脂肪、血脂HDL-C均显著下调,盐酸罗格列酮处理组脂肪酶显著升高;脂肪组织中JAK2、STAT3、PPARγ和Leptin mRNA表达量显著降低,FAS mRNA表达量极显著降低,HSL mRNA表达量无变化;肝脏中STAT3、FAS、PPARγ、Leptin mRNA表达量显著降低。盐酸罗格列酮组(C组)脂肪组织中STAT3和PPARγmRNA表达量显著增高,其它基因无变化;肝脏组织中通路基因和脂代谢基因均无显著变化。
The janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway participate in many signal transduction systems, influencing cell growth, survival, apoptosis, stress and differentiation functions. Adipose plays a critical role in energy balance as essential tissue in energy metabolism. If lipid matbolism disorder happens, there will be many pathological changes in body. As transcription factors, Fatty acid synthetase (FAS) is a key enzyme in lipogenesis. Peroxisome proliferator-activated receptor (PPARγ) is known to regulate expression of many enzymes. Hormone-sensitive lipase (HSL) was ever seemed as the only enzyme in lipolysis. Leptin is an important regulator of the energy balance. In this study, these factors and enzymes are detected on transcription level in mice adipose tissue, liver and adipocyte, which were treated by AG490 and rosiglitazone. We also analysised the correlation between JAK2/STAT3 signaling pathway and the expression lipid metabolism′s gene (FAS、PPARγ、Leptin and HSL), The main results were summarized as following:
1. Fed with normal diet, in the AG490 treated group, the body weight of mice decreased significantly, the deposition of epididymal adipose reduced, the content of high density lipoprotein cholesterol (HDL-C) in serum decreased, the activity of lypase increased compared with control. In adipose tissue, the expression levels of JAK2 and STAT3 decreased significantly as well as FAS and Leptin, however, there were no significant change for the expression of PPARγand HSL; the expression level of JAK2 and STAT3 in liver were also down-regulated.
In the chlorhydric acid rosiglitazone treated group, the activity of liver lipase increased significantly, however, no obvious changes were found for mice body weight, epididymal adipose deposition as well as the contents of TG, HDL-C,TC in the serum. In adipose tissue, there were no change for the expression of JAK2 and STAT3, the expression level of FAS decreased significantly; the expression level of PPARγincreased significantly, no expression changes were found for FAS, Leptin and HSL.
2. Fed with high fat diet, in the AG490 treated group, the mice body weight began to decrease significantly at the seventh day, and the significant level lasted for about 7days. Compared with control, the deposition of epididymal adipose and the contents of TG, TC, and HDL-C in serum were significantly lower; the expression level of FAS mRNA decreased extremely significantly; no changes were found for the expression of PPARγand Leptin. The expression levels of JAK2/STAT3 signal pathway related genes in liver tissue were the same with that of adipose tissue. The expression level of PPARγand HSL mRNA decreased significantly, no changes were found for the expression of FAS and Leptin.
In the chlorhydric acid rosiglitazone treated group, the activity of liver lipase increased significantly, the expression level of JAK2 mRNA decreased significantly both in the liver and adipose tissue. There were significant decrease for the expression of FAS and HSL in adipose tissue, the expression of PPARγmRNA increased significantly, no change was found about the expression level of FAS; In liver, the expression of FAS decreased significantly, no expression change were found for other genes.
3. Obese-model mice fed with normal diet, compared with control,in the AG490 treated group, the body weight, the deposition of epididymal adipose, as well as the content of HDL-C in serum decreased significantly. In the chlorhydric acid rosiglitazone treated group,in adipose tissue, the activity of lypase increased significantly, the expression levels of JAK2, STAT3, PPARγ,and Leptin mRNA decreased significantly, and the expression of FAS decreased extremely significantly, no change was found for the expression of HSL mRNA; in liver, the expression levels of STAT3, FAS, PPARγand Leptin mRNA decreased significantly. In the chlorhydric acid rosiglitazone treated group, in adipose tissue, the expression levels of STAT3 and PPARγmRNA increased significantly, no changes were found for other genes; in liver, no significant changes were found for the signal pathway related genes as well as the lipid metabolism related genes.
1.饲喂普通日粮下,AG490处理组小鼠体重显著降低,附睾脂肪沉积减少,血脂指标中HDL-C含量降低,脂肪酶活性升高。在脂肪组织中,JAK2和STAT3基因转录水平显著下调,同时FAS和Leptin基因转录水平显著降低,但PPARγ和HSL基因表达无显著变化;肝脏中JAK2和STAT3基因转录也明显下调。
盐酸罗格列酮处理组小鼠肝脏脂肪酶活性显著升高,而体重、附睾脂肪含量、血脂指标均无明显变化;在脂肪组织中,JAK2和STAT3基因转录无变化,而FAS转录显著降低,PPARγ基因转录极显著升高,Leptin和HSL基因表达无变化;肝脏中仅PPARγ基因表达量上升,FAS、Leptin和HSL基因表达量无变化。
2.高脂日粮饲喂下,AG490处理组小鼠体重在第7天开始显著下降,到第14天依然保持显著状态,附睾脂肪、血脂指标均显著低于对照组;脂肪组织中JAK2、STAT3和HSL mRNA表达量显著降低,FAS mRNA表达量极显著降低,PPARγ和Leptin mRNA表达量无变化;肝脏中JAK2/STAT3通路基因mRNA表达变化同脂肪组织一致,PPARγ和HSL mRNA表达量显著降低,FAS和Leptin mRNA表达量无变化。
盐酸罗格列酮处理组肝脏脂肪酶显著升高;脂肪组织和肝脏中JAK2 mRNA表达量均显著降低,脂肪组织中FAS和HSL mRNA表达量显著降低,PPARγmRNA表达量显著增高,Leptin mRNA表达量无变化;肝脏中仅FAS mRNA表达量显著降低外,其它基因无变化。
3.肥胖模型小鼠在普通日粮饲喂情况下,AG490处理组小鼠体重、附睾脂肪、血脂HDL-C均显著下调,盐酸罗格列酮处理组脂肪酶显著升高;脂肪组织中JAK2、STAT3、PPARγ和Leptin mRNA表达量显著降低,FAS mRNA表达量极显著降低,HSL mRNA表达量无变化;肝脏中STAT3、FAS、PPARγ、Leptin mRNA表达量显著降低。盐酸罗格列酮组(C组)脂肪组织中STAT3和PPARγmRNA表达量显著增高,其它基因无变化;肝脏组织中通路基因和脂代谢基因均无显著变化。
The janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway participate in many signal transduction systems, influencing cell growth, survival, apoptosis, stress and differentiation functions. Adipose plays a critical role in energy balance as essential tissue in energy metabolism. If lipid matbolism disorder happens, there will be many pathological changes in body. As transcription factors, Fatty acid synthetase (FAS) is a key enzyme in lipogenesis. Peroxisome proliferator-activated receptor (PPARγ) is known to regulate expression of many enzymes. Hormone-sensitive lipase (HSL) was ever seemed as the only enzyme in lipolysis. Leptin is an important regulator of the energy balance. In this study, these factors and enzymes are detected on transcription level in mice adipose tissue, liver and adipocyte, which were treated by AG490 and rosiglitazone. We also analysised the correlation between JAK2/STAT3 signaling pathway and the expression lipid metabolism′s gene (FAS、PPARγ、Leptin and HSL), The main results were summarized as following:
1. Fed with normal diet, in the AG490 treated group, the body weight of mice decreased significantly, the deposition of epididymal adipose reduced, the content of high density lipoprotein cholesterol (HDL-C) in serum decreased, the activity of lypase increased compared with control. In adipose tissue, the expression levels of JAK2 and STAT3 decreased significantly as well as FAS and Leptin, however, there were no significant change for the expression of PPARγand HSL; the expression level of JAK2 and STAT3 in liver were also down-regulated.
In the chlorhydric acid rosiglitazone treated group, the activity of liver lipase increased significantly, however, no obvious changes were found for mice body weight, epididymal adipose deposition as well as the contents of TG, HDL-C,TC in the serum. In adipose tissue, there were no change for the expression of JAK2 and STAT3, the expression level of FAS decreased significantly; the expression level of PPARγincreased significantly, no expression changes were found for FAS, Leptin and HSL.
2. Fed with high fat diet, in the AG490 treated group, the mice body weight began to decrease significantly at the seventh day, and the significant level lasted for about 7days. Compared with control, the deposition of epididymal adipose and the contents of TG, TC, and HDL-C in serum were significantly lower; the expression level of FAS mRNA decreased extremely significantly; no changes were found for the expression of PPARγand Leptin. The expression levels of JAK2/STAT3 signal pathway related genes in liver tissue were the same with that of adipose tissue. The expression level of PPARγand HSL mRNA decreased significantly, no changes were found for the expression of FAS and Leptin.
In the chlorhydric acid rosiglitazone treated group, the activity of liver lipase increased significantly, the expression level of JAK2 mRNA decreased significantly both in the liver and adipose tissue. There were significant decrease for the expression of FAS and HSL in adipose tissue, the expression of PPARγmRNA increased significantly, no change was found about the expression level of FAS; In liver, the expression of FAS decreased significantly, no expression change were found for other genes.
3. Obese-model mice fed with normal diet, compared with control,in the AG490 treated group, the body weight, the deposition of epididymal adipose, as well as the content of HDL-C in serum decreased significantly. In the chlorhydric acid rosiglitazone treated group,in adipose tissue, the activity of lypase increased significantly, the expression levels of JAK2, STAT3, PPARγ,and Leptin mRNA decreased significantly, and the expression of FAS decreased extremely significantly, no change was found for the expression of HSL mRNA; in liver, the expression levels of STAT3, FAS, PPARγand Leptin mRNA decreased significantly. In the chlorhydric acid rosiglitazone treated group, in adipose tissue, the expression levels of STAT3 and PPARγmRNA increased significantly, no changes were found for other genes; in liver, no significant changes were found for the signal pathway related genes as well as the lipid metabolism related genes.
引文
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