On the role and fate of LPS-dephosphorylating activity in the rat liver
On the role and fate of LPS-dephosphorylating activity in the rat liver
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DOI：
10.1152/ajpgi.00147.2005
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发表时间：
2006-02-01
影响因子：
4.5
通讯作者：
Poelstra, K
中科院分区：
文献类型：
--
作者：
Tuin, A;Huizinga-Van der Vlag, A;Poelstra, K
肠源性脂多糖(LPS)在纤维化等肝病的发病机制中起着重要作用。碱性磷酸酶(AP)存在于肠壁和肝脏等组织中，先前已被证明能使内毒素去磷酸化。因此，我们研究了内毒素对肝脏AP表达的影响以及AP对内毒素诱导的肝细胞反应的影响。在正常和纤维化动物肝细胞管膜上均有脂多糖去磷酸化活性的表达。除此之外，纤维化动物在胆管周围也表现出很高的内毒素去磷酸化活性。该酶可使几种细菌中的内毒素脱磷。脂多糖本身在2小时内迅速增加了肝脏内该酶的mRNA水平，提高了7倍。此外，体外和体内研究表明，外源性肠道AP迅速与肝细胞上的去唾液酸糖蛋白受体结合。该肠道异构体在体外显著减弱了脂多糖诱导的肝肿瘤坏死因子-α和一氧化氮(亚硝酸盐和硝酸盐)的反应。在体内，该酶还能减少脂多糖诱导的肝糖原分解。这项研究表明，内毒素增强了肝细胞中AP的表达，而肠道AP迅速被这些细胞摄取，导致体内内毒素诱导的反应减弱。因此，肠道来源的内毒素去磷酸化活性或肝细胞内的酶上调可能是肝脏内的一种保护机制。
Gut-derived lipopolysaccharide (LPS) plays a role in the pathogenesis of liver diseases like fibrosis. The enzyme alkaline phosphatase (AP) is present in, among others, the intestinal wall and liver and has been previously shown to dephosphorylate LPS. Therefore, we investigated the effect of LPS on hepatic AP expression and the effect of AP on LPS-induced hepatocyte responses. LPS-dephosphorylating activity was expressed at the hepatocyte canalicular membrane in normal and fibrotic animals. In addition to this, fibrotic animals also displayed high LPS-dephosphorylating activity around bile ducts. The enzyme was shown to dephosphorylate LPS from several bacterial species. LPS itself rapidly enhanced the intrahepatic mRNA levels for this enzyme within 2 h by a factor of seven. Furthermore, in vitro and in vivo studies showed that exogenous intestinal AP quickly bound to the asialoglycoprotein receptor on hepatocytes. This intestinal isoform significantly attenuated LPS-induced hepatic tumor necrosis factor-alpha and nitric oxide (nitrite and nitrate) responses in vitro. The enzyme also reduced LPS-induced hepatic glycogenolysis in vivo. This study shows that LPS enhances AP expression in hepatocytes and that intestinal AP is rapidly taken up by these same cells, leading to an attenuation of LPS-induced responses in vivo. Gut-derived LPS-dephosphorylating activity or enzyme upregulation within hepatocytes by LPS may therefore be a protective mechanism within the liver.