Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice
Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice
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DOI：
10.3109/00365521.2011.613945
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发表时间：
2011-11-01
影响因子：
1.9
通讯作者：
De Souza, Claudio T.
中科院分区：
文献类型：
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作者：
Frederico, Marisa J. S.;Vitto, Marcelo F.;De Souza, Claudio T.
Objective.本研究探讨了固醇调节元件结合蛋白（SREBP-1c）和相关蛋白在肥胖小鼠（DIO）中的水平，用SREBP-1c反义寡核苷酸（阿索）治疗，以观察脂肪变性的逆转。材料和方法。用含有61 kJ%饱和脂肪的食物喂养Swiss小鼠8周以发展肥胖。在此期间之后，使用一组动物通过免疫印迹分析在剂量-反应曲线（0; 1.0; 2.0; 3.0; 4.0 nmol/天）中评估SREBP-1c反义寡核苷酸处理的分子效应。剂量（3.0 nmol/天）确定后，另一组治疗14天。最后一次注射后24小时后，处死小鼠，获得血浆和肝组织，以评价血浆甘油三酯和总肝脂肪。进行Western印迹以评价SREBP-1c、FAS、SCD-1、PPAR γ和CPT 1表达以及AMPK[Thr 172]和ACC[Ser 79]磷酸化。使用苏木精和伊红方法对肝脏进行染色以进行组织学分析。结果体重、附睾脂肪和葡萄糖水平不受阿索每日一次给药的影响。然而，总血浆甘油三酯和总肝脏脂肪显著降低。此外，这种治疗抑制SREBP-1c并降低一系列参与脂肪生成的蛋白质的蛋白质水平，包括ACC，FAS和SCD-1。此外，用阿索处理的小鼠表现出肝脏脂肪变性的宏观和微观特征的显著减少。结论我们的研究结果表明，抑制SREBP-1c降低了脂肪生成酶的表达，减少了甘油三酯的积累，最终逆转了小鼠的肝脏脂肪变性。
Objective. The present study investigates the level of Sterol-regulatory element-binding proteins (SREBP-1c) and related proteins in obese mice (DIO) treated with SREBP-1c antisense oligonucleotide (ASO) to observe a reversal of steatosis. Materials and methods. Swiss mice were fed on chow containing 61 kJ% saturated fat for 8 weeks to develop obesity. After this period, one group of animals was used to assess the molecular effects of SREBP-1c antisense oligonucleotide treatment by immunoblot analysis in a dose-response curve (0; 1.0; 2.0; 3.0; 4.0 nmol/day). After the dose (3.0 nmol/day) was determined, another group was treated for 14 days. After a period of 24 h following the last injection mice were killed and plasma and hepatic tissue were obtained to evaluate plasma triglycerides and total liver fat. Western blot was performed to evaluate SREBP-1c, FAS, SCD-1, PPAR gamma and CPT1 expression and AMPK[Thr172] and ACC[Ser79] phosphorylation. Livers were stained using the hematoxylin and eosin method for histological analysis. Results. Body weight, epididymal fat and glucose levels were not affected by one daily dose of ASO. However, total plasma triglycerides and total liver fat were significantly reduced. Also, this treatment inhibited SREBP-1c and reduced protein levels of a series of proteins involved in lipogenesis, including ACC, FAS and SCD-1. Moreover, mice treated with ASO presented a significant reduction in macroscopic and microscopic features of hepatic steatosis. Conclusion. Our results demonstrate that the inhibition of SREBP-1c decreased the expression of lipogenic enzymes, reducing the accumulation of triglycerides and, finally, reversing hepatic steatosis in mice.