LPS transport during fat absorption is inhibited in caveolin-1 knockout murine jejunum.

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.