Elastin, the major protein of the extracellular matrix, is specially found in cardiovascular tissues and contributing to 30–50% of the dry weight of blood vessels. Elastin regulates cell signalling pathways involved in morphogenesis, injury response and inflammation. The function of elastin is frequently compromised in damaged or aged elastic tissues. Indeed, elastin degradation, observed during ageing, and the resulting production of elastin-derived peptides (EDPs), have crucial impacts on cardiovascular disease (atherosclerosis, thrombosis) or on metabolism disease progressions (type 2 diabetes or non-alcoholic steatohepatitis). In the present study, we analysed the EDP effects on 3T3 preadipocyte cell differentiation. In a first part, we treated 3T3-L1 cells with EDP and visualized the lipid droplet accumulation by the oil red O staining and measured the expression of various transcription factors and adipocyte-specific mRNAs by real-time RT-PCR. We demonstrated that the elastin receptor complex, ERC, is activated by EDPs and decreased adipocyte differentiation by a modulation of crucial adipogenesis transcriptional factor particularly PPARγ. In a second part, we identified the signalling pathway implicated in EDP-reduced cell differentiation. The flow cytometry and immunocytochemistry approaches showed that ERC activated by EDP produced a second messenger, lactosylceramide (Lac-Cer). Moreover, this Lac-Cer production favoured the phosphorylation of ERK1–2 (p-ERK1–2), to decrease adipocyte differentiation by a modulation of adipogenesis transcriptional factor PPARγ. To conclude, the EDP/Lac-Cer/p-ERK1–2 signalling pathway may be studied further as a critical target for treating complications associated with adipocyte dedifferentiation such as obesity and diabetes insulin resistance.

中文翻译：

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弹性蛋白衍生肽诱导的乳糖基神经酰胺降低了脂肪细胞的分化。

弹性蛋白是细胞外基质的主要蛋白质，特别存在于心血管组织中，占血管干重的30％至50％。弹性蛋白调节参与形态发生，损伤反应和炎症的细胞信号通路。弹性蛋白的功能经常在受损或老化的弹性组织中受损。实际上，在衰老过程中观察到的弹性蛋白降解以及由此产生的弹性蛋白衍生肽（EDPs）对心血管疾病（动脉粥样硬化，血栓形成）或新陈代谢疾病的进展（2型糖尿病或非酒精性脂肪性肝炎）具有至关重要的影响。在本研究中，我们分析了EDP对3T3前脂肪细胞分化的影响。在第一部分中 我们用EDP处理3T3-L1细胞，并通过油红O染色观察脂质滴的积累，并通过实时RT-PCR测量各种转录因子和脂肪细胞特异性mRNA的表达。我们证明，弹性蛋白受体复合物ERC被EDP激活，并通过调节重要的脂肪生成转录因子（特别是PPARγ）而降低了脂肪细胞分化。在第二部分中，我们确定了与EDP减少的细胞分化有关的信号通路。流式细胞仪和免疫细胞化学方法显示，EDP激活的ERC产生了第二种信使，乳糖酰神经酰胺（Lac-Cer）。此外，这种Lac-Cer产生有利于ERK1-2（p-ERK1-2）的磷酸化，通过调节脂肪生成转录因子PPARγ来减少脂肪细胞分化。