Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice.
Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice.
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DOI：
10.1186/1476-511x-11-121
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发表时间：
2012-09-19
影响因子：
4.5
通讯作者：
Yamazaki K
中科院分区：
文献类型：
--
作者：
Miyazawa H;Tabeta K;Miyauchi S;Aoki-Nonaka Y;Domon H;Honda T;Nakajima T;Yamazaki K
牙周病被认为通过诱发血脂异常而增加动脉粥样硬化血栓性疾病的风险。最近，我们证明前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 在调节循环低密度脂蛋白 (LDL) 胆固醇水平中发挥关键作用，在牙周炎患者中升高。然而，牙周炎患者 PCSK9 升高的潜在机制尚不清楚。在这里，我们利用动物模型探讨了牙龈卟啉单胞菌（一种代表性的牙周病细菌）诱导的炎症反应是否调节血清 PCSK9 和胆固醇水平。我们用牙周病细菌的代表性菌株牙龈卟啉单胞菌腹腔感染 C57BL/6 小鼠，并评估血清 PCSK9 水平和血清脂质谱。在肝脏中检查了 PCSK9 和 LDL 受体 (LDLR) 基因和蛋白质表达，以及肝脏 X 受体 (Lxrs)、LDLR 诱导降解剂 (Idol) 和甾醇调节元件结合转录因子 (Srebf)2 基因表达。与假感染小鼠相比，牙龈卟啉单胞菌感染引起血清 PCSK9 水平显着升高，并伴随总胆固醇和 LDL 胆固醇升高。 LDL胆固醇水平与PCSK9水平显着相关。与假感染小鼠相比，牙龈卟啉单胞菌感染小鼠肝脏中 Pcsk9、Ldlr 和 Srebf2 基因的表达上调。尽管已知 Pcsk9 基因表达受甾醇调节元件结合蛋白 (SREBP)2（Srebf2 的人类同源物）正向调节，而 Srebf2 受胆固醇负向调节，但在感染小鼠中发现的 Srebf2 表达升高被认为是由牙龈卟啉单胞菌感染介导的。牙龈卟啉单胞菌感染通过上调 Srebf2 上调 PCSK9 的产生，与胆固醇水平无关。需要进一步的研究来阐明感染如何调节 Srebf2 表达并随后影响脂质代谢。
Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models. We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver. P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection. P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.