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蓝莓联合益生菌通过IL-22调控的JAK1/STAT3/BAX通路改善非酒精性脂肪性肝病的作用机制
Mechanism of action of blueberry combined with probiotics in improving nonalcoholic fatty liver disease by affecting the JAK1/STAT3/BAX signaling pathway regulated by interleukin-22
文章发布日期:2018年08月06日  来源:  作者:祝娟娟,程明亮,赵雪珂,等  点击次数:242次  下载次数:8次

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【摘要】:目的研究蓝莓联合益生菌通过对IL-22调控的JAK1/STAT3/BAX信号通路的影响,进一步探明其改善非酒精性脂肪性肝病(NAFLD)的作用机制。方法清洁级SD大鼠40只分为正常对照组(CG)、IL-22siRNA阴性对照组 (IL-22SI-NC)、IL-22siRNA组(IL-22SI)、IL-22siRNA阴性对照+蓝莓益生菌组(IL-22SI-NC+BPG)、IL-22siRNA+蓝莓益生菌组(IL-22SI+BPG)。正常对照组予100%普通饮食,其余大鼠均采用复合高脂饲料制备脂肪肝模型,同时予IL-22siRNA阴性对照慢病毒及IL-22siRNA慢病毒腹部肝区注射(盲穿),隔日1次,共12周,取肝脏确认造模及siRNA封闭效果后予蓝莓益生菌原液灌胃,同时按上述分组后给予正常饮食,予蓝莓益生菌原液灌胃,共观察8周。多组间比较采用单因素方差分析,进一步比较方差齐时采用SNK法(q检验),方差不齐时用Tamhane法(q′检验)。结果IL-22SI组与IL-22SI-NC组比较,ALT、AST、TC、TG、LDL均显著升高(P值均<0.01),HDL显著降低(P<0.01),IL-22、JAK1、STAT3的mRNA及蛋白表达均明显减弱(P值均<0.01)、BAX的表达明显升高(P<0.01);与IL-22SI-NC相比,IL-22SI-NC+BPG的ALT、AST、TC、TG、LDL均明显降低(P值均<0.01),HDL明显升高(P<0.01),IL-22、JAK1、STAT3的mRNA及蛋白表达均显著升高(P值均<0.01),BAX的表达显著下降(P<0.01);IL-22SI+BPG较IL-22SI组ALT、AST、TC、TG、LDL均略有降低(P值均<0.05),HDL略有升高(P<0.05), IL-22、JAK1、STAT3的mRNA及蛋白表达均有所增加(P值均<0.05),BAX的表达略有减少(P<0.05)。结论 蓝莓联合益生菌能一定程度拮抗IL-22siRNA所加剧的肝细胞脂肪变性,并可以增强IL-22的表达,提示IL-22可能为蓝莓联合益生菌影响NAFLD的关键作用因子。推测蓝莓联合益生菌能增强IL-22表达,激活JAK1/STAT3信号通路,抑制其下游凋亡因子BAX的表达,减少肝细胞凋亡,增强胆固醇代谢,减少脂质沉积,达到改善NAFLD的目的,是NAFLD的一个辅助治疗方案。
【Abstract】:ObjectiveTo investigate the effect of blueberry combined with probiotics on the JAK1/STAT3/BAX signaling pathway regulated by interleukin-22 (IL-22) and their mechanism of action in improving nonalcoholic fatty liver disease (NAFLD). MethodsA total of 40 clean Sprague-Dawley rats were divided into normal control group (CG group), IL-22 siRNA-negative control group (IL-22SI-NC group), IL-22 siRNA group (IL-22SI group), IL-22 siRNA-negative control+blueberry-probiotics group (IL-22SI-NC+BPG group), and IL-22 siRNA+blueberry-probiotics group (IL-22SI+BPG group). The rats in the CG group were given 100% normal diet, and the rats in all the other groups were given compound high-fat diet to establish a rat model of fatty liver and were then given the injection of IL-22 siRNA-negative control lentivirus or IL-22 siRNA lentivirus at the abdominal liver area (blind puncture) every other day for 12 weeks in total. The liver was harvested to confirm whether the model was established successfully or not and the effect of siRNA, and then the above groups were given normal diet and blueberry-probiotics solution by gavage. The rats were observed for 8 weeks. One-way analysis of variance was used for comparison between multiple groups; the SNK test (q test) was used for further pairwise comparisons of data with homogeneity of variance, while the Tamhane′s test (q′ test) was used for the data with heterogeneity of variance. ResultsCompared with the IL-22SI-NC group, the IL-22SI group had significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) (all P<0.01), a significant reduction in high-density lipoprotein (HDL) (P<0.01), significant reductions in the mRNA and protein expression of IL-22, JAK1, and STAT3 (all P<0.01), and a significant increase in the expression of Bcl-2-associated X protein (BAX) (P<0.01). Compared with the IL-22SI-NC group, the IL-22SI-NC+BPG group had significant reductions in ALT, AST, TC, TG, and LDL (all P<0.01), a significant increase in HDL (P<0.01), significant increases in the mRNA and protein expression of IL-22, JAK1, and STAT3 (all P<0.01), and a significant reduction in BAX (P<0.01). Compared with the IL-22SI group, the IL-22SI+BPG group had significant reductions in ALT, AST, TC, TG, and LDL (all P<0.05), a significant increase in HDL (P<0.05), significant increases in the mRNA and protein expression of IL-22, JAK1, and STAT3 (all P<0.05), and a significant reduction in BAX (P<0.05). ConclusionBlueberry combined with probiotics can antagonize hepatocyte fatty degeneration accelerated by IL-22 siRNA to a certain degree and increase the expression of IL-22, indicating that IL-22 may be a key factor for blueberry combined with probiotics in improving NAFLD. It is speculated that blueberry combined with probiotics can enhance the expression of IL-22, activate the JAK1/STAT3 signaling pathway to inhibit the expression of the downstream apoptotic factor BAX, reduce hepatocyte apoptosis, increase cholesterol metabolism, reduce lipid deposition, and thus improve NAFLD. Therefore, it is considered an adjuvant therapeutic regimen for NAFLD.
【关键字】:非酒精性脂肪性肝病; 白细胞介素10; 有益菌种; 蓝莓; Janus激酶1; 转录激活因子3; bcl-2相关X蛋白质
【Key words】:non-alcoholic fatty liver disease; interleukin-10; probiotics; blueberry; janus kinase 1; activating transcription factor 3; bcl-2-associated X protein
【引证本文】:ZHU JJ, CHENG ML, ZHAO XK, et al. Mechanism of action of blueberry combined with probiotics in improving nonalcoholic fatty liver disease by affecting the JAK1/STAT3/BAX signaling pathway regulated by interleukin-22[J]. J Clin Hepatol, 2018, 34(9): 1936-1944. (in Chinese)
祝娟娟, 程明亮, 赵雪珂, 等. 蓝莓联合益生菌通过IL-22调控的JAK1/STAT3/BAX通路改善非酒精性脂肪性肝病的作用机制[J]. 临床肝胆病杂志, 2018, 34(9): 1936-1944.

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