Diabetes downregulates peptide transporter 1 in the rat jejunum: possible involvement of cholate-induced FXR activation
Peptide transporter 1 (PepT1), highly expressed on the apical membrane of enterocytes, is involved in energy balance and mediates intestinal absorption of peptidomimetic drugs. In this study, we investigated whether and how diabetes affected the function and expression of intestinal PepT1. Diabetes was induced in rats by combination of high-fat diet and low dose streptozocin injection. Pharmacokinetics study demonstrated that diabetes significantly decreased plasma exposures of cephalexin and acyclovir following oral administration of cephalexin and valacyclovir, respectively. Single-pass intestinal perfusion analysis showed that diabetes remarkably decreased cephalexin absorption, which was associated with decreased expression of intestinal PepT1 protein. We assessed the levels of bile acids in intestine of diabetic rats, and found that diabetic rats exhibited significantly higher levels of chenodeoxycholic acid (CDCA), cholic acid (CA) and glycocholic acid (GCA), and lower levels of lithocholic acid (LCA) and hyodeoxycholic acid (HDCA) than control rats; intestinal deoxycholic acid (DCA) levels were unaltered. In Caco-2 cells, the 6 bile acids remarkably decreased expression of PepT1 protein with CDCA causing the strongest inhibition, whereas TNF-α, LPS and insulin little affected expression of PepT1 protein; short-chain fatty acids induced rather than decreased expression of PepT1 protein. Farnesoid X receptor (FXR) inhibitor glycine-β-muricholic acid or FXR knockdown reversed the downregulation of PepT1 expression by CDCA and GW4064 (another FXR agonist). In diabetic rats, the expression of intestinal FXR protein was markedly increased. Oral administration of CDCA (90, 180 mg·kg −1 ·d −1 , for 3 weeks) dose-dependently decreased the expression and function of intestinal PepT1 in rats. In conclusion, diabetes impairs the expression and function of intestinal PepT1 partly via CDCA-mediated FXR activation.