Lipopolysaccharide transport during long-chain fatty acid exposure is mediated by caveolin-1 dependent endocytosis in murine jejunum

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The entry of bacterial-derived lipopolysaccharides (LPS) from the intestinal lumen to the circulation induces low-grade systemic inflammation. We have found that LPS is transcellularly transported to the portal vein during luminal long-chain fatty acid (LCFA) exposure via CD36- and lipid raft-mediated pathways in rat jejunum, consistent with the involvement of caveolae-mediated endocytosis. We thus examined LPS transport in wild-type (WT) and caveolin-1 (Cav1) knockout (KO) murine jejunum. FITC-LPS was added to the mucosal bath of Ussing chambered muscle-stripped jejunal mucosa of WT and Cav1KO mice. Serosal appearance of FITC-LPS was measured with or without luminal application of oleic acid (OA, 10 mM) with taurocholic acid (TCA, 0.1 mM), or medium-chain fatty acid (MCFA) sodium caprate (C10, 30 mM). Luminal application of OA/TCA increased FITC-LPS m-to-s transport in WT jejunum, inhibited by the CD36 inhibitor sulfosuccinimidyl oleate or lipid raft inhibitor methyl-β-cyclodextrin, though not by the clathrin inhibitor chlorpromazine or Pitstop2, suggesting that LCFA-induced LPS transport is mediated by caveolae-mediated endocytosis. In contrast, OA/TCA-induced FITC-LPS transport was abolished in Cav1KO jejunum. Nevertheless, luminal C10 increased FITC-LPS transport in both WT and Cav1KO jejuna without transepithelial electrical resistance changes. Chlorpromazine and Pitstop2 inhibited C10-induced FITC-LPS transport, suggesting that C10 enhances transcellular LPS transport via clathrin-mediated endocytosis in the jejunum. These results suggest that LPS transport during LCFA exposure is mediated by Cav1-mediated endocytosis, whereas MCFA-induced LPS transport is via clathrin-mediated endocytosis. Modulation of epithelial endocytosis may be a new therapeutic target for the prevention of dietary lipid -associated endotoxemia, including the metabolic syndrome.

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