EFFECT OF ENDOTOXIN ON BILE-ACID TRANSPORT IN RAT-LIVER - A POTENTIALMODEL FOR SEPSIS-ASSOCIATED CHOLESTASIS

Intrahepatic cholestasis in the setting of extrahepatic bacterial infe ction has been attributed to the effects of endotoxin and cytokines su ch as tumor necrosis factor-alpha (TNF-alpha) on bile acid transport. To define the mechanism of sepsis-associated cholestasis, taurocholate transport was examined in basolateral (bLPM) and canalicular (cLPM) r at liver plasma membrane vesicles derived from control and endotoxin [ lipopolysaccharide (LPS)]-treated animals and in plasma membrane vesic les prepared after TNF-alpha treatment. Na+-dependent [H-3]taurocholat e uptake and both membrane-potential-dependent and ATP-dependent [H-3] taurocholate transport were reduced in bLPM and cLPM vesicles, respect ively, after LPS treatment. In membrane vesicles from TNF-alpha-treate d animals, Na+-dependent [H-3]taurocholate uptake was also reduced. No rthern blot hybridization, using cDNA probes for the putative sinusoid al bile acid transporter (Ntcp) and canalicular ecto-adenosinetriphosp hatase, demonstrated decreased mRNA levels after LPS and TNF-alpha tre atment. Immunoblot analysis of membrane extracts from LPS-treated anim als revealed decreased levels of these putative bile acid transporters . Impaired bile acid transport at the sinusoidal and canalicular membr ane domains by these and other mediators of the inflammatory response may account for sepsis-associated cholestasis.