ABSTRACT
Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Δhepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Δhepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Δhepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-ß (TGFß), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Cytokine Receptor gp130/metabolism , Hepatocytes/metabolism , Animals , Carcinoma, Hepatocellular/chemically induced , Cytokine Receptor gp130/genetics , DNA Damage/drug effects , DNA Damage/genetics , Diethylnitrosamine/toxicity , Female , Flow Cytometry , Fluorescent Antibody Technique , Hepatocytes/drug effects , Immunoblotting , Inflammation/genetics , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oncostatin M/toxicity , Oxidative Stress/drug effects , Oxidative Stress/genetics , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolismABSTRACT
Steatotic liver grafts are associated with a high incidence of primary nonfunction and initial poor function. Due to the increasing number of liver transplant candidates, centers are inclined to accept marginal donors more frequently. For a lack of a reliable fatty liver model, preservation concepts for fatty livers have hardly been evaluated. Moreover, there is an ongoing debate on the relevance and impact of micro- versus macrovesicular steatotic organs. We therefore intended to establish a steatotic liver model in pigs comprising both micro- and macrovesicular steatotic livers. Five groups of pigs received daily 1 to 6 g ethanol/kg body weight and/or a protein-deficient diet for up to 72 days. Liver biopsy was carried out at days 24, 48, and 72. With an increasing amount and duration of ethanol intake, higher levels of microvesicular steatosis were induced. Ethanol and protein deficient diet resulted in more than 60% microvesicular steatosis after 72 days. Exclusively protein-deficient diet without ethanol induced macrovesicular steatosis of more than 70% after 72 days. For the first time, we established a porcine model of hepatic steatosis that comprises both histologic types of fatty liver: micro- and macrovesicular steatosis induced by ethanol and a protein-deficient diet. We would like to conclude that our model is particularly qualified to study new concepts of preservation for steatotic livers to improve on the posttransplant outcome.
