Growth hormone modulation of the rat hepatic bile transporter system in endotoxin-induced cholestasis.
Treatment with high dose human GH, although an effective anabolic agent, has been associated with increased incidence of sepsis, inflammation, multiple organ failure, and death in critically ill patients. We hypothesized that GH might increase mortality by exacerbating cholestasis through modulation of bile acid transporter expression. High dose GH was continuously infused over 4 d into rats, and on the final day lipopolysaccharides were injected. Hepatic bile acid transporter expression was measured by Northern analysis and immunoblotting and compared with serum markers of cholestasis and endotoxinemia. Compared with non-GH-treated controls, GH increased endotoxin-induced markers of cholestasis and liver damage as well as augmented IL-6 induction. In endotoxinemia, GH treatment significantly induced multidrug resistance-associated protein 1 mRNA and protein and suppressed organic anion transporting polypeptides, Oatp1 and Oatp4, mRNA, suggesting impaired uptake of bilirubin and bile acids at the basolateral surface of the hepatocyte, which could contribute to the observed worsening of cholestasis by GH. This study of endotoxinemia may thus provide a mechanistic link between GH treatment and exacerbation of cholestasis through modulation of basolateral bile acid transporter expression in the rat hepatocyte.
Mesotten
Dieter
D
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. dieter.mesotten@med.kuleuvehn.ac.be
Van den Berghe
Greet
G
Liddle
Christopher
C
Coulter
Sally
S
McDougall
Fiona
F
Baxter
Robert C
RC
Delhanty
Patric J D
PJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D015415:Biomarkers; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D015870:Gene Expression; D013006:Growth Hormone / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D027981:Symporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D002352:Carrier Proteins; D051544:Cytochrome P-450 CYP3A; D013006:Growth Hormone; D006913:Hydroxysteroid Dehydrogenases; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D012964:Sodium; D027981:Symporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490280:SLC22A7 protein, human; C088800:Slc22a7 protein, rat; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter; C095122:multidrug resistance protein 3; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C465260:Cyp3a2 protein, rat