Growth hormone modulation of the rat hepatic bile transporter system in endotoxin-induced cholestasis.

Abstract	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.
Authors	Dieter Mesotten, Greet Van den Berghe, Christopher Liddle, Sally Coulter, Fiona McDougall, Robert C Baxter, Patric J D Delhanty
Journal	Endocrinology (Endocrinology) Vol. 144 Issue 9 Pg. 4008-17 (Sep 2003) ISSN: 0013-7227 [Print] United States
PMID	12933675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	ATP Binding Cassette Transporter, Subfamily B ATP-Binding Cassette Transporters Biomarkers Carrier Proteins Lipopolysaccharides Membrane Glycoproteins Membrane Proteins Membrane Transport Proteins Organic Anion Transport Protein 1 Organic Anion Transporters, Sodium-Dependent Organic Anion Transporters, Sodium-Independent SLC22A7 protein, human Slc22a7 protein, rat Symporters bile acid binding proteins sodium-bile acid cotransporter Growth Hormone multidrug resistance protein 3 Sodium Hydroxysteroid Dehydrogenases AKR1C2 protein, human Aryl Hydrocarbon Hydroxylases Cyp3a2 protein, rat Cytochrome P-450 CYP3A
Topics	ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism) ATP-Binding Cassette Transporters (genetics, metabolism) Animals Aryl Hydrocarbon Hydroxylases (genetics, metabolism) Bile (metabolism) Biomarkers Carrier Proteins (genetics, metabolism) Cholestasis, Intrahepatic (chemically induced, metabolism) Cytochrome P-450 CYP3A Gene Expression Growth Hormone (pharmacology) Hepatocytes (drug effects, metabolism) Hydroxysteroid Dehydrogenases Lipopolysaccharides (pharmacology) Liver (cytology, drug effects, metabolism) Male Membrane Glycoproteins Membrane Proteins Membrane Transport Proteins Organic Anion Transport Protein 1 (genetics, metabolism) Organic Anion Transporters, Sodium-Dependent Organic Anion Transporters, Sodium-Independent (genetics, metabolism) Rats Rats, Sprague-Dawley Sepsis (metabolism) Sodium (metabolism) Symporters ATP-Binding Cassette Sub-Family B Member 4

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