The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis
The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis
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DOI：
10.1152/ajpgi.00317.2012
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发表时间：
2013-01-01
影响因子：
4.5
通讯作者：
Halpern, Melissa D.
中科院分区：
文献类型：
--
作者：
Cherrington, Nathan J.;Estrada, Teresa E.;Halpern, Melissa D.
肝胆汁酸转运体Ntcp和Mrp2在实验性坏死性小肠结肠炎中下调。[J] .中国生物医学工程学报，2013,31(4):448 - 456。首次发表于2012年11月1日；doi: 10.1152 / ajpgi.00317.2012。坏死性小肠结肠炎（NEC）是早产儿最常见的胃肠道急症，其特征是回肠远端和结肠近端出现广泛的出血性炎症性坏死。我们之前的研究表明，在实验性NEC的发展过程中，肝脏在调节回肠炎症中起着重要作用，回肠胆汁酸（BA）的积累以及回肠胆汁酸转运体的失调导致回肠损伤。鉴于这些发现，我们推测在实验性NEC中，肝脏BA转运蛋白也会发生改变。使用大鼠和小鼠NEC模型，研究了Cyp7a1、Cyp27a1和肝BA转运体Bsep、Ntcp、Oatp2、Oatp4、Mrp2和Mrp3的水平。此外，当促炎细胞因子肿瘤坏死因子(TNF)- α和白细胞介素(IL)-18在NEC中升高，在疾病发展过程中被中和时，肝脏BA转运蛋白的水平也被确定。Ntcp和Mrp2在NEC中减少，但回肠BA水平升高与这些减少无关。然而，tnf - α的中和使Ntcp正常化，而IL-18的去除使Mrp2水平正常化。这些数据表明，在NEC啮齿动物模型中，肝脏转运蛋白Ntcp和Mrp2下调，而Cyp27a1升高。此外，实验性NEC中tnf - α和IL-18水平的升高可能分别参与Ntcp和Mrp2的调控。这些数据表明，在制定NEC的治疗方式时应考虑肠-肝轴。
The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 304: G48-G56, 2013. First published November 1, 2012; doi: 10.1152/ajpgi.00317.2012.-Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants and is characterized by an extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. We have previously shown that, during the development of experimental NEC, the liver plays an important role in regulating inflammation in the ileum, and accumulation of ileal bile acids (BA) along with dysregulation of ileal BA transporters contributes to ileal damage. Given these findings, we speculated that hepatic BA transporters would also be altered in experimental NEC. Using both rat and mouse models of NEC, levels of Cyp7a1, Cyp27a1, and the hepatic BA transporters Bsep, Ntcp, Oatp2, Oatp4, Mrp2, and Mrp3 were investigated. In addition, levels of hepatic BA transporters were also determined when the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-18, which are both elevated in NEC, are neutralized during disease development. Ntcp and Mrp2 were decreased in NEC, but elevated ileal BA levels were not responsible for these reductions. However, neutralization of TNF-alpha normalized Ntcp, whereas removal of IL-18 normalized Mrp2 levels. These data show that the hepatic transporters Ntcp and Mrp2 are downregulated, whereas Cyp27a1 is increased in rodent models of NEC. Furthermore, increased levels of TNF-alpha and IL-18 in experimental NEC may play a role in the regulation of Ntcp and Mrp2, respectively. These data suggest the gut-liver axis should be considered when therapeutic modalities for NEC are developed.