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车叶草苷对非酒精性脂肪性肝病大鼠肝纤维化的影响及机制
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| 篇名： | 车叶草苷对非酒精性脂肪性肝病大鼠肝纤维化的影响及机制 |
| TITLE： | Effect and mechanism of asperuloside on liver fibrosis in non-alcoholic fatty liver rats |
| 摘要： | 目的 探究车叶草苷调节鞘氨醇激酶1（SphK1）/1-磷酸鞘氨醇（S1P）信号通路对非酒精性脂肪性肝病（NAFLD）大鼠肝纤维化的影响及机制。方法以高脂饲料饲养的方法建立大鼠NAFLD模型，将造模成功的大鼠随机分为模型组、车叶草苷低剂量组（14mg/kg，灌胃，下同）、车叶草苷高剂量组（28mg/kg）、车叶草苷高剂量（28mg/kg）+pc-NC（空载质粒，50µg，尾静脉注射，下同）组、车叶草苷高剂量（28mg/kg）+pc-SphK1（SphK1过表达质粒，50µg）组，每组12只。另取12只大鼠以正常饲料饲养作为对照组。各组大鼠灌胃或尾静脉注射相应药物或质粒，灌胃处理每天1次，尾静脉注射处理每周2次，均连续3周。末次给药后，检测各组大鼠血脂指标[总胆固醇（TC）、甘油三酯（TG）、游离脂肪酸（FFA）]与肝功能指标[天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）]水平；观察大鼠肝组织病理变化以及肝纤维化情况；检测大鼠血清纤维化相关因子[Ⅲ型前胶原（PCⅢ）、Ⅳ型胶原（Ⅳ-Col）、层粘连蛋白（LN）]、促纤维化因子[转化生长因子β（1TGF-β1）]与促炎因子[白细胞介素1β（IL-1β）、诱导型一氧化氮合酶（iNOS）、IL-6]水平；检测大鼠肝组织胶原形成相关蛋白（Ⅰ-Col、Ⅳ-Col）与SphK1/S1P信号通路相关蛋白表达。结果与对照组比较，模型组大鼠肝组织呈现明显病理损伤症状；NAFLD活动度评分、肝组织胶原容积分数（CVF）和血清中TC、TG、FFA、AST、ALT、PCⅢ、Ⅳ-Col、LN、TGF-β1、IL-1β、iNOS、IL-6水平以及肝组织中Ⅰ-Col、Ⅳ-Col、SphK1、S1P蛋白表达水平均显著升高（P＜0.05）。与模型组比较，车叶草苷低、高剂量组大鼠肝组织病理损伤症状均减轻，上述指标水平均显著降低（P＜0.05），且高剂量组降低效果更好（P＜0.05）。与车叶草苷高剂量组和车叶草苷高剂量+pc-NC组比较，车叶草苷高剂量+pc-SphK1组大鼠肝组织病理损伤症状加重，上述指标水平均显著升高（P＜0.05）。结论车叶草苷可通过抑制SphK1/S1P信号通路活性，降低促纤维化因子、促炎因子以及胶原形成蛋白表达，从而减轻NAFLD大鼠肝纤维化。 |
| ABSTRACT： | OBJECTIVE To investigate the effect and mechanism of asperuloside on liver fibrosis in non-alcoholic fatty liver disease （NAFLD） rats by regulating the sphingosine kinase 1 （SphK1）/sphingosine-1-phosphate （S1P） signaling pathway. METHODS SD rats were fed with a high-fat diet to establish a NAFLD model. They were randomly separated into model group， asperuloside low-dose group （14 mg/kg， i.g.， similarly hereinafter）， asperuloside high-dose group （28 mg/kg）， high dose of asperuloside （28 mg/kg）+pc-NC （empty plasmid， 50 µg， via tail vein， similarly hereinafter） group， and high dose of asperuloside （28 mg/kg）+pc-SphK1 （SphK1 overexpression plasmid， 50 µg） group， with 12 rats in each group. Another 12 rats were fed with a normal diet as control group. Each group was given relevant medicine or plasmid intragastrically once a day or via tail vein twice a week， for 3 consecutive weeks. After the last medication， the levels of blood lipid indexes [total cholesterol （TC）， triglyceride （TG）， and free fatty acid （FFA）] and liver function indexes [aspartate transaminase （AST） and alanine transaminase （ALT）] were detected in each group. The pathological changes of liver tissue and liver fibrosis in rats were also observed in each group. The levels of serum fibrosis-related factors [procollagen type Ⅲ （PCⅢ）， collagen type Ⅳ （Ⅳ-Col）， laminin （LN）]， pro-fibrotic factor [transforming growth factor-β1 （TGF-β1）]， and pro-inflammatory factors [interleukin-1β （IL-1β）， inducible nitric oxide synthase （iNOS）， IL-6] of rats were determined in each group. The expressions of collagen formation-related proteins （Ⅰ-Col， Ⅳ-Col） and SphK1/S1P pathway-related proteins in the liver tissues of rats were detected in each group. RESULTS Compared with control group， the liver tissue of rats in model group showed significant pathological damage； the NAFLD activity score， liver tissue collagen volume fraction， serum levels of TC，TG， FFA， AST， ALT， PCⅢ， Ⅳ-Col， LN， TGF-β1， IL-1β， iNOS and IL-6， and protein expressions of Ⅰ-Col， Ⅳ-Col， SphK1 and S1P in liver tissue were greatly increased （P＜0.05）. Compared with the model group， the liver tissue pathological damage symptoms of rats in asperuloside low-dose and high-dose groups were improved， and the above indexes were all reduced significantly （P＜0.05）； moreover， the high-dose group had a better effect （P＜0.05）. Compared to asperuloside high-dose group， high dose of asperuloside+pc-NC group， the pathological damage of liver tissue symptoms in rats were aggravated in high dose of asperuloside+pc-SphK1 group， and the above indexes were all increased significantly （P＜0.05）. CONCLUSIONS Asperuloside can reduce the expressions of pro-fibrotic factor， pro-inflammatory factors and collagen formation-related proteins by inhibiting the activity of SphK1/S1P signaling pathway， thus alleviating liver fibrosis in NAFLD rats. |
| 期刊： | 2024年第35卷第17期 |
| 作者： | 梁金；许丹；杜进军 |
| AUTHORS： | LIANG Jin，XU Dan，DU Jinjun |
| 关键字： | 车叶草苷；非酒精性脂肪性肝病；肝纤维化；SphK1/S1P信号通路 |
| KEYWORDS： | asperuloside； non-alcoholic fatty liver disease； liver fibrosis； SphK1/S1P signaling pathway |
| 阅读数： | 7 次 |
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