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Growth Hormone Modulation of the Rat Hepatic Bile Transporter System in Endotoxin-Induced Cholestasis

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital (D.M., F.M., R.C.B., P.J.D.D.), St. Leonards, New South Wales 2065, Australia; Department of Intensive Care Medicine, University Hospital Gasthuisberg, Catholic University of Leuven (D.M., G.V.d.B.), B-3000 Leuven, Belgium; and Department of Clinical Pharmacology, Westmead Millennium Institute, University of Sydney, Westmead Hospital (C.L., S.C.), Westmead, New South Wales 2145, Australia

Address all correspondence and requests for reprints to: Dr. Dieter Mesotten, Department of Intensive Care Medicine, University Hospital Gasthuisberg, B-3000 Leuven, Belgium. E-mail: dieter.mesotten{at}med.kuleuven.ac.be.

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.

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				M. Wood, M. Ananthanarayanan, B. Jones, R. Wooton-Kee, T. Hoffman, F. J. Suchy, and M. Vore Hormonal Regulation of Hepatic Organic Anion Transporting Polypeptides Mol. Pharmacol., July 1, 2005; 68(1): 218 - 225. [Abstract] [Full Text] [PDF]