Abstract 108: Consequences of hepatic JAK2 deficiency for liver metabolism and hepatocarcinogenesis

Abstract

Abstract The metabolic syndrome is a frequent disease in the western world due to increased prevalence of obesity and diabetes mellitus. Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome associated with primary stages of hepatocellular carcinoma (HCC). Hepatic JAK2-STAT5 signaling is mainly activated by growth hormone (GH) which controls cellular metabolism. To address the role of hepatic JAK2 in lipid homeostasis and hepatocarcinogenesis, we crossed a mouse model of inflammatory liver cancer caused by hyperactivated GH signaling (GHtg) to mice harboring the hepatocyte-specific deletion of JAK2 (J2KO; using AlfpCre). While excess of GH caused chronic hepatitis, as well as pathologic alterations such as big hepatocytes with large polymorphic nuclei, severe and progressive hepatosteatosis was evident in GHtg:J2KO and J2KO mice as soon as 12 weeks of age. Hepatosteatosis in JAK2 deficient mice, independent of GH overexpression, was due to increased hepatic lipid synthesis and peripheral lipolysis associated with elevated unsaturated fatty acid (FA) and triglyceride (TG) amounts in the liver. However, microvesicular steatosis, which is associated with a more severe pathology, was more abundant in GHtg:J2KO livers accompanied by significantly elevated liver/body weight ratios. Surprisingly, loss of hepatic JAK2 proteins led to delayed hepatocarcinogenesis in aged mice. Currently, we are investigating the involvement of NAFLD in the pathogenesis of HCC development by genetic and histo-pathologic profiling. We will provide molecular and cellular insights responsible for delayed hepatocarcinogenesis in GHtg:J2KO and J2KO mice. Citation Format: Madeleine Themanns, Katrin Friedbichler, Sonja M. Kessler, Michaela Schlederer, Lukas Kenner, Kay-Uwe Wagner, Johannes Haybaeck, Richard Moriggl. Consequences of hepatic JAK2 deficiency for liver metabolism and hepatocarcinogenesis. [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 108. doi:10.1158/1538-7445.AM2014-108