Uncoupling of Biliary Lipid From Bile Acid Secretion by Formyl– Methionyl–Leucyl–Phenylalanine in the Rat

Abstract

A neutrophil chemotactic factor N–formyl–methionyl–leucyl–phenylalanine (fMLP), produced by Escherichia coli under conditions of intestinal inflammation, is reported to circulate enterohepatically in the presence of experimental colitis, but its effect on bile secretion is unclear. Therefore, we investigated the effect of fMLP on bile secretion in a single–pass isolated perfused rat liver system. Infusion of fMLP at different concentrations (2 μmol/L, 10 μmol/L, and 20 μmol/L) into the portal vein resulted in excretion into bile in the native form, independent of sodium taurocholate (1 μmol/min) infusion. Excretion of fMLP increased dose dependently, and approximately 12% of the infused dose was detected at each concentration. With constant infusion of sodium taurocholate (1 μmol/min), fMLP (20 μmol/L) increased bile flow but decreased phospholipid and cholesterol secretion. Bile acid secretion was not affected. Phospholipid/bile acid molar ratios decreased from 0.069 ± 0.002 to 0.038 ± 0.002, and cholesterol/bile acid molar ratios decreased from 0.0074 ± 0.0009 to 0.0029 ± 0.0008. Thus, administration of fMLP resulted in the uncoupling of biliary excretion of phospholipid and cholesterol from that of bile acids; this effect proved reversible. The increase in bile flow caused by fMLP infusion appeared to result from osmotic choleresis. When 25 mg of horseradish peroxidase, a conventional marker of transcytotic vesicle transport pathway, was infused for 1 minute as a pulse load into the portal vein after continuous infusion of taurocholate, its late peak excretion was reduced by fMLP (10 μmol/L) from 9.59 ± 1.09 to 6.05 ± 0.66 (ng/g liver). Gel–permeation chromatography of bile showed a specific association of fMLP with bile acids. These results suggest an uncoupling of biliary lipids from bile acids by fMLP because of inhibition of transcellular vesicle transport and interaction between fMLP and bile acid micelles in the bile canaliculus.