On the role and fate of LPS-dephosphorylating activity in the rat liver.
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.
Tuin
Annemarie
A
Department of Pharmacokinetics and Drug Delivery, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.tuin@rug.nl
Huizinga-Van der Vlag
Ali
A
van Loenen-Weemaes
Anne-Miek M A
AM
Meijer
Dirk K F
DK
Poelstra
Klaas
K
D000469:Alkaline Phosphatase / Q000378:metabolism*; D000818:Animals; D024061:Collagen Type III / Q000378:metabolism; D020895:Enterocytes / Q000201:enzymology; D005943:Gluconeogenesis / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D024061:Collagen Type III; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D012313:RNA; D000469:Alkaline Phosphatase