582 Teduglutide Inhibits Sodium Caprate-Induced Clathrinmediated LPS Transport in Rat Jejunum (original) (raw)

in intestinal epithelial cells and in mouse intestine via a transcriptional mechanism. We speculate that CP-induced decrease in PAT-1 function and expression may contribute to a higher occurrence of nephrolithiasis in immunocompromised patients. (Supported by NIDDK and Department of Veterans Affairs) 582 TEDUGLUTIDE INHIBITS SODIUM CAPRATE-INDUCED CLATHRIN-MEDIATED LPS TRANSPORT IN RAT JEJUNUM Yasutada Akiba, Jonathan D. Kaunitz Lipopolysaccharides (LPS) entry from the intestinal lumen to the circulation is associated with systemic inflammation. We have found that LPS is transcellularly transported to the portal vein (PV) during luminal perfusion with long-chain fatty acid (LCFA) via CD36-and lipid raft-mediated pathways, which are inhibited by and the stable glucagon-like peptide-2 (GLP-2) analog teduglutide (TDG). We examined the effects of medium-chain fatty acids (MCFA) on LPS transport in rat jejunum. FITC-LPS was applied to the mucosal bath of Ussing chambered muscle-stripped jejunal and distal colonic mucosa-submucosa preparations, in which short-circuit current (I sc) and tissue electrical resistance (TER) were measured. Serosal appearance of FITC-LPS was measured with or without luminal application of sodium caprate (C10, 10 mM). FITC-dextran 4kDa (FD4) m-to-s movement was also separately measured. The effects of serosal GLP-2 (100 nM) with a dipeptidyl peptidase 4 inhibitor NVP728 (10 µM) or TDG (10 µg/ml) on C10-mediated FITC-LPS transport were also examined. Luminal application of C10 increased FITC-LPS m-to-s transport without any changes in FD4 m-to-s movement and TER in the jejunum, whereas C10 increased FITC-LPS transport with increased FD4 movement and decreased TER in the distal colon, suggesting that C10 enhances transcellular LPS transport in the jejunum, but increases paracellular permeability in the distal colon. In the jejunum, C10-mediated FITC-LPS m-to-s transport was inhibited by pretreatment with luminal Pitstop2 (30 µM), a selective inhibitor of clathrinmediated endocytosis (CME), whereas the CD36 inhibitor sulfosuccinimidyl oleate (SSO, 0.1 mM), the lipid raft inhibitor methyl-b-cyclodextrin (MbCD, 1 mM), or the dynamin inhibitor Dynasore (50 µM) had no effect. In contrast, luminal OA (30 mM) with taurocholate (TCA, 0.1 mM) also increased FITC-LPS transport with SSO, MbCD and Dynasore-sensitive, but Pitstop2-insensitive manner. Serosal application of GLP-2 with NVP728 or TDG abolished C10-mediated FITC-LPS transport. Furthermore, serosal pretreatment of VIP (30 nM) or a nitric oxide donor (S)-Nitroso-N-acetylpenicillamine SNAP (0.1 mM) reduced C10-mediated FITC-LPS transport, suggesting that GLP-2-induced reduction of LPS transport is mediated via VIP and NO pathways. In vivo, jejunal luminal perfusion of C10 (10 mM) with FITC-LPS increased PV FITC-LPS appearance 15 min after perfusion, which was inhibited by coperfusion of Pitstop2. These results suggest that luminal MCFA and LCFA differentially induce transcellular LPS transport in the jejunum; MCFA via CME, but LCFA via the CD36/ lipid raft/caveolin pathway. GLP-2 and TDG inhibited MCFA-induced LPS transport possibly via VIP and NO pathways. Dietary fatty acids may exacerbate LPS-associated diseases, including the metabolic syndrome and multiple organ failure, that can be treated with TDG.