Growth hormone resistance exacerbates cholestasis‐induced murine liver fibrosis. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Stiedl, Patricia; McMahon, Robert; Blaas, Leander; Stanek, Victoria; Svinka, Jasmin; Grabner, Beatrice; Zollner, Gernot; Kessler, Sonja M.; Claudel, Thierry; Müller, Mathias; Mikulits, Wolfgang; Bilban, Martin; Esterbauer, Harald; Eferl, Robert; Haybaeck, Johannes; Trauner, Michael; Casanova, Emilio
• Is Part Of: Hepatology. Volume 61:Issue 2(2015:Feb.)
• Page Start: 613
• Page End: 626
• Publication Date: 2015-02
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27408
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="hep27408-sec-0001" sec-type="section"> <p>Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the GH receptor gene (Ghr<sup>–/–</sup>, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2<sup>–/–</sup>), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr<sup>–/–</sup>;Mdr2<sup>–/–</sup> mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation, and increased collagen deposition relative to Mdr2<sup>–/–</sup> mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr<sup>–/–</sup>;Mdr2<sup>–/–</sup> mice had a pronounced down‐regulation of hepatoprotective genes <italic>Hnf6</italic>, <italic>Egfr</italic>, and <italic>Igf‐1</italic>, and significantly increased levels of reactive oxygen species (ROS) and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr<sup>–/–</sup>) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis, and bile infarcts compared to their wild‐type littermates, indicating that loss of <italic>Ghr</italic> renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr<sup>–/–</sup>;Mdr2<sup>–/–</sup> mice displayed a significant decrease in tumor incidence compared to Mdr2<sup>–/–</sup> mice, indicating that loss of <italic>Ghr</italic> signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. <italic>Conclusion</italic>: GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. (H<sc>epatology</sc> 2015;61:613‐626)</p> </sec> </abstract>