UNCOUPLING OF BILIARY LIPID FROM BILE-ACID SECRETION BY FORMYL-METHIONYL-LEUCYL-PHENYLALANINE IN THE RAT

A neutrophil chemotactic factor N-formyl-methionylleucyl-phenylalanine (fMLP), produced by Escherichia coli under conditions of intestinal i nflammation, is reported to circulate enterohepatically in the presenc e 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 d ifferent concentrations (2 mu mol/L, 10 mu mol/L, and 20 mu mol/L) int o the portal vein resulted in excretion into bile in the native form, independent of sodium taurocholate (1 mu mol/min) infusion, Excretion of fMLP increased dose dependently, and approximately 12% of the infus ed dose was detected at each concentration. With constant infusion of sodium taurocholate (1 mu mol/min), fMLP (20 mu mol/L) increased bile now but decreased phospholipid and cholesterol secretion, Bile acid se cretion was not affected, Phospholipid/bile acid molar ratios decrease d from 0.069 +/- 0.002 to 0.038 +/- 0.002, and cholesterol/bile acid m olar ratios decreased hom 0.0074 +/- 0.0009 to 0.0029 +/- 0.0008. Thus , administration of fMLP resulted in the uncoupling of biliary excreti on of phospholipid and cholesterol from that of bile acids; this effec t 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 p athway, 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 mu mol/L) from 9.59 +/- 1.09 to 6.05 +/- 0.66 (ng /g liver). Gel-permeation chromatography of bile showed a specific ass ociation of fMLP with bile acids. These results suggest an uncoupling of biliary lipids from bile acids by fMLP because of inhibition of tra nscellular vesicle transport and interaction between fMLP and bile aci d micelles in the bile canaliculus.