HFHS Cav1 data.xlsx

The entry of lipopolysaccharides (LPS) from the intestinal lumen to the circulation is considered essential for the metabolic syndrome (MetS). We have reported that LPS is transcellularly transported from the jejunal lumen in the presence of luminal long-chain fatty acid (LCFA) via caveolin-1 (Cav1)-mediated endocytotic pathways. Here, we examined the effects of diets of varying FA composition on the MetS induction and LPS transport in murine jejunum.

Male and female C57Bl6 wild type (WT) and global Cav1 knockout (KO) mice were fed a standard diet (SD), or one of 3 high fat/high sucrose diets enriched in saturated LCFA (LCD), medium-chain FA (MCD) and polyunsaturated FA (PUD) for 6 wks. FITC-LPS or FITC-dextran (FD4) m-to-s transport with transepithelial electrical resistance (TEER) was measured in Ussing chambers.

MetS was predominantly induced in male WT LCD with increased portal venous LPS levels, but less strongly induced in WT MCD and PUD or in KO. Interestingly, basal FITC-LPS and FD4 transport was increased in the jejunum of male WT LCD without TEER change, compared with WT SD, but not in KO LCD. The LCD-induced enhanced LPS and FD4 transports were abolished by luminal inhibitors of lipid rafts, CD36, or Src kinase. In vivo imaging demonstrated intracellular vesicular uptake of dextran and LPS in the jejunal villous enterocytes with absent paracellular staining in male WT LCD, but not in WT SD or KO LCD. In proximal colonic mucosa, there was no LPS or FD4 transport in WT SD or LCD.

These results suggest that LCD constitutively activates Cav1-mediated endocytotic LPS transport in the small intestine, with consequent metabolic endotoxemia and MetS. Cav1-mediated LPS transport is a promising therapeutic target for diet-induced, LPS-associated MetS.