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小檗碱(BBR)具有多种药理活性。己有的研究表明BBR不仅可以通过拮抗HSP70-TNFα降低高热所引起的体温升高,还可以对抗低温所引起的体温降低。但是对于后者的分子机制尚不十分清楚。因此,我们以产热重要因子UCP1(uncoupling protein 1)为对象,对于BBR在低温条件下的作用机制进行了研究。本研究分别使用了野生型和Ucp1–/–基因敲除小鼠进行整体动物实验,使用原代脂肪细胞和HIB-1B细胞系进行体外实验。低温条件控制在4°C。结果表明,低温条件下小鼠体温明显下降,BBR可以明显的抑制这种体温的下降。同时小鼠棕色脂肪组织中Ucp1表达升高,BBR则进一步促进其表达。然而,Ucp1–/–基因敲除小鼠中BBR的抑制体温降低的作用消失,表明Ucp1基因是BBR防治低温时体温降低的主要靶点。进一步研究表明,Ucp1基因转录启动区上游转录响应元件NFE2(nuclear factor erythroid-derived 2)具有增强Ucp1基因表达的作用。BBR与NFE2的结合有温度依赖性。低温时,BBR与NFE2的亲和力明显增强,从而促进Ucp1基因的表达。本研究对于认识BBR通过作用于棕色脂肪进行产热、调节体温以及提高低温耐受性具有重要的意义。
Berberine (BBR) has a variety of pharmacological activities. Some researches have shown that BBR not only can reduce body temperature caused by hyperthermia by antagonizing HSP70-TNFα, but also can fight hypothermia caused by hypothermia. However, the molecular mechanism of the latter is not yet clear. Therefore, we investigated the mechanism of action of BBR at low temperature with uncoupling protein 1 (UCP1), an important factor of thermogenesis. In this study, wild-type and Ucp1 - / - knockout mice were used for whole animal experiments, using primary adipocytes and HIB-1B cell lines in vitro experiments. Low temperature conditions are controlled at 4 ° C. The results showed that the body temperature was significantly decreased in mice at low temperature, BBR can significantly inhibit the decline of this body temperature. At the same time, the expression of Ucp1 in mouse brown adipose tissue increased, BBR further promoted its expression. However, the inhibition of BBR in Ucp1 - / - knockout mice disappeared, indicating that the Ucp1 gene is the main target of BBR for preventing hypothermia when exposed to low temperature. Further studies showed that Ucp1 gene transcription initiation region upstream transcription response element NFE2 (nuclear factor erythroid-derived 2) has enhanced the Ucp1 gene expression. The binding of BBR to NFE2 is temperature-dependent. At low temperatures, BBR affinity with NFE2 significantly increased, thereby promoting the expression of Ucp1 gene. This study is of great significance for understanding the role BBR plays in the production of brown fat by thermogenesis, regulating body temperature and improving the tolerance to low temperature.