Growth hormone resistance and liver fibrosis

Liver fibrosis constitutes a considerable health problem in the human population. Growth hormone resistance syndrome has been largely associated with liver cirrhosis in humans and it has been considered as a mere consequence of liver dysfunction attributed to fibrosis. Challenging this view, we propose that growth hormone resistance actively contributes to the onset and development of fibrosis. To address this question, we generated compound knockout mice by crossing growth hormone receptor knockout animals (Ghr-/-, a mouse model for growth hormone resistance) with a mouse strain of inflammatory cholestasis and liver cancer (Mdr2-/- mice). Animals lacking both, MDR2 and GHR display severe liver fibrosis at 3-8 weeks characterized by a massive hepatic collagen deposition. This data suggest that growth hormone resistance plays an active role in the development of liver fibrosis rather than just being a consequence of the disease. Within this proposal, we will address the connection between growth hormone resistance and liver fibrosis, reversibility of liver fibrosis and progression of liver fibrosis to hepatocellular carcinoma.

Liver cirrhosis is a devastating disease which may progress into liver cancer and it is strongly linked to modern life style. It is a considerable health problem in industrialized countries and its incidence is rising in developing countries. Liver cirrhosis is caused by chronic liver damage triggered by infections (e.g. hepatitis), alcohol consume, obesity, bile duct malfunctioning and toxins (e.g. aflatoxins produced by diverse fungi). Chronic liver damage results in the death of hepatocytes and their replacement by scar tissue. If the primary insult continues the liver may slowly deteriorate resulting in liver malfunction, liver failure and death. In addition, frequently liver cirrhosis may progress to liver cancer (hepatocellular carcinoma), which is also a deadly disease. Unfortunately, current treatment options for liver cirrhosis are limited to the removal of the primary insult or to liver transplantation in advanced cirrhosis. Therefore, the development of new therapies to treat liver cirrhosis is a medical and social need. The Growth hormone (GH)-Insulin-like growth factor 1 (IGF1) axis is responsible of many physiological processes in the liver, as for example the regulation of metabolism, hepatocyte proliferation, hepatocyte survival, etc. Since long time, it has been observed a correlation between malfunctioning of the GH-IGF1 axis and the development of liver cirrhosis. Within this project, we have studied this connection by employing several experimental models of impaired GH-IGF1 axis and liver cirrhosis. Interestingly, we have found that the GH-IGF1 axis protects from liver fibrosis. Indeed, blockade of the GH-IGF1 axis increased the sensitivity of hepatocytes to insults, resulting in increased cell death and faster development of liver fibrosis. Thus, we have identified the GH-IGF1 axis as a crucial signaling pathway which safeguards from liver cirrhosis and opened the possibility to manipulate the GH-IGF1 axis to develop new therapies to treat liver cirrhosis.