Luminal LPS is transported across murine small intestine by a caveolin-1 dependent endocytic mechanism induced by chronic feeding of a Western-style diet.

Metabolic endotoxemia is an important risk factor for the metabolic syndrome (MetS). We report that lipopolysaccharides (LPS) are transcellularly transported from the jejunal lumen during long-chain fatty acids (LCFA) absorption via caveolin (Cav)-1-mediated endocytosis. Here, we examined the effects of diets of varying fatty acid (FA) composition on the induction of MetS and LPS transport. We fed wild-type (WT) and Cav-1 knockout (KO) mice with a standard diet (SD), or one of three high-fat/high-sucrose diets enriched with saturated LCFA, medium-chain FA, or polyunsaturated FA, measuring FITC-LPS or FITC-dextran (FD4) mucosa-to-serosa transport in the jejunum and colon. MetS rapidly developed in the male WT LCFA diet group with increased portal endotoxemia, less so in WT other dietary groups or in KO mice. Interestingly, in male WT LCFA, increased basal FITC-LPS and FD4 transport was observed without electrical resistance change. Lipid rafts, CD36, or Src kinase inhibitors abolished LCFA diet-induced increase of LPS/FD4 transport, with intracellular vesicular uptake of dextran and LPS in male WT LCFA diet group observed. Chronic feeding of a Western-style diet tonically activates endocytic LPS transport in the small intestine via a Cav-1-dependent mechanism, leading to MetS. This novel mechanism reveals several novel targets for inhibiting LPS uptake.