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 in rats, suggesting the involvement of caveolae-mediated endocytosis. We thus examined LPS transport in caveolin-1 (Cav1) knockout (KO) murine jejunum.
FITC-LPS was applied to the mucosal bath of Ussing chambered muscle-stripped jejunal mucosa-submucosa preparations of Cav1 KO and wild type (WT) mice. Serosal appearance of FITC-LPS was measured with or without luminal application of oleic acid (OA, 30 mM) with taurocholic acid (TCA, 0.1 mM), or medium-chain fatty acid sodium caprate (C10, 10 mM).
Luminal application of OA/TCA increased FITC-LPS m-to-s transport in WT jejunum, inhibited by the CD36 inhibitor sulfosuccinimidyl oleate (SSO, 0.1 mM) or the lipid raft inhibitor methyl-β-cyclodextrin (MβCD, 0.1 mM), not by the clathrin inhibitor chlorpromazine (0.1 mM) or Pitstop2 (30 µM), suggesting that LCFA-induced LPS transport is mediated by caveolae-mediated endocytosis, not by clathrin-mediated endocytosis. In contrast, OA/TCA-induced FITC-LPS transport was abolished in Cav1 KO jejunum. Nevertheless, luminal application of C10 increased FITC-LPS transport both in WT and Cav1 KO jejuna without transepithelial electrical resistance changes, suggesting that C10 enhances transcellular LPS transport via caveolin-independent 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 likely via clathrin-mediated endocytosis. Modulation of epithelial endocytosis may be a new therapeutic target for LPS-associated diseases mediated by dietary fatty acids, including metabolic syndrome.
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