Sodium Caprate Enhances Transcellular LPS Transport via Clathrin‐Mediated Endocytosis in Rat Jejunum

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Lipopolysaccharides (LPS) entry from the intestinal lumen to the circulation is associated with systemic inflammation. We have found that LPS is transcellularly transported to portal vein during long‐chain fatty acid (LCFA) exposure via CD36‐ and lipid raft‐mediated pathways. 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 (Isc) 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.Luminal application of caprate increased FITC‐LPS m‐to‐s transport without any changes in FD4 m‐to‐s movement and TER in the jejunum, whereas caprate remarkably increased FITC‐LPS transport with increased FD4 movement and decreased TER in the distal colon, suggesting that caprate 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 clathrin‐mediated endocytosis (CME), whereas the CD36 inhibitor sulfosuccinimidyl oleate (SSO, 0.1 mM), the lipid raft inhibitor methyl‐β‐cyclodextrin (MβCD, 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, MβCD and Dynasore‐sensitive, but Pitstop2‐insensitive manner. In vivo, jejunal luminal perfusion of C10 with FITC‐LPS increased portal venous FITC‐LPS appearance 15 min after perfusion, higher than by OA/TCA, which was then inhibited by co‐perfusion 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. Dietary fatty acids may impact LPS‐associated diseases, including metabolic disease and multiple organ failure.Support or Funding InformationVA Merit Review and Shire Pharmaceuticals