Abstract 5349: The role of growth hormone receptor in liver fibrosis and cancer

Abstract

Abstract Liver fibrosis is defined as the pathological excessive deposition of extracellular matrix proteins which contributes to a disruption of normal liver architecture. Fibrosis can progress to cirrhosis, which can eventually result in hepatocellular carcinoma. Over the past decades our understanding of the cellular and molecular mechanisms of liver fibrosis has advanced greatly. Activated hepatic stellate cells, myofibroblasts of bone marrow origin and portal fibroblasts have all been identified as major contributors to fibrosis. Recently, growth hormone resistance and low serum levels of IGF-1 have also been associated with liver cirrhosis in humans, indicating a role for growth hormone receptor, which itself controls various cellular functions including the transcription of IGF-1 through Stat 5 signaling. Furthermore, supplementation of recombinant IGF-1 in cirrhotic animal models was shown to reduce disease severity. In order to elucidate whether the GHR plays an active role in the establishment of fibrotic liver diseases or rather represents a major consequence of this illness, we crossed mice lacking the Ghr/bp gene (Ghr -/-) with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Our results show that Ghr-/-;Mdr2-/- mice display deregulated bile acid homeostasis and increased serum markers associated with inflammation and fibrosis. Bile duct proliferation and extensive collagen deposition were also observed in Ghr-/-;Mdr2-/- relative to Mdr2-/- mice. Additionally, compared to control mice a pronounced down regulation of the hepato-protective genes Hnf6, Egfr and Igf-1 was seen in Ghr-/-;Mdr2-/- animals, which also displayed significantly increased apoptosis. Moreover, single knockout mice (Ghr-/-) developed bile infacts when fed with 1% cholic acid compared to their wildtype littermates, indicating that loss of GHR renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly and despite their severe fibrotic phenotype Ghr -/-; Mdr2 -/- mice showed a significant decrease in tumor incidence compared to Mdr2 -/- mice, indicating that loss of GHR signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. Our findings suggest that loss of GHR signaling results in increased liver injury in the Mdr2 -/- mouse model of inflammatory cholestasis and liver fibrosis, signifying the possible therapeutic value of this pathway in the development of liver fibrosis treatments. Citation Format: Patricia Stiedl, Leander Blaas, Viktoria Stanek, Jasmin Svinka, Robert Mc Mahon, Gernot Zollner, Thierry Claudel, Mathias Mueller, Wolfgang Mikulits, Harald Esterbauer, Robert Eferl, Johannes Haybaeck, Michael Trauner, Emilio Casanova. The role of growth hormone receptor in liver fibrosis and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5349. doi:10.1158/1538-7445.AM2014-5349