The physiopathological bases of the hepatic response to acute and chronic injury: mechanisms of disease progression

The liver plays key roles in many processes which are central to the homeostasis of the organism. It is responsible for the metabolism of nutrients, the storage and distribution of carbohydrates, fats and vitamins, and the synthesis of essential plasma proteins such as albumin, acute phase proteins and coagulation factors. The liver is also the most important organ for the detoxification of drugs, xenobiotics and potentially toxic metabolites, and is also the target of hepatotropic viruses such as hepatitis B and C viruses. These tasks may entail the exposure of liver cells to a wide range of harmful agents, however under normal conditions and to a certain extent a healthy liver can cope with this and avoid injury and cell loss. However, when liver defensive capacities are exceeded and death of parenchymal cells occurs a potent regenerative and wound healing reaction is triggered. Chronic liver injury and inflammation results in the fibrotic degeneration of the liver parenchyma and the development of cirrhosis, the end-stage of liver disease and the background on which most hepatocellular carcinomas (HCC) develop.

Our research focuses on the study of liver responses to acute and chronic injury, and the mechanisms involved in the progression of liver injury from metabolic alterations, fibrogenesis, hepatocellular dedifferentiation and oncogenesis. We implement a combined molecular and physiopathological approach in order to address the following objectives:
-    The identification of new factors (cytokines, growth factors, metabolites) involved in the endogenous defensive response of the liver during injury and regeneration. Such factors may be developed into hepatoprotective strategies.
-    The study of the mechanisms that participate in hepatocellular dedifferentiation and liver fibrogenesis in chronic liver damage.
-    The study of HCC cell biology, with the aim of identifying new molecular targets to quell tumor cell growth and metastasis.

More specifically, our latest contributions in this field can be summarized as follows:

In collaboration with the Laboratory of Oncobiology, headed by Dr. Carmen Berasain:

1. Identification of new mechanisms involved in hepatic regeneration and in the endogenous defense of the liver against damage
•    We have demonstrated the hepatoprotective potential of the interleukin-6 family cytokine cardiotrophin-1 during ischemia-reperfusion liver injury.
•    We have shown for the first time the essential role played by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AR) during liver regeneration. Our observations identified AR as a novel mitogen for the hepatocyte and as a potent cytoprotective growth factor during acute liver injury.

2. Study of the mechanisms involved in the progression of liver disease: from inflammation to liver fibrosis and HCC development
•    We have described a new role for the transcription factor Wilms’ tumor gene-1 (WT1) in the progression of liver disease. We found that WT1 gene expression is upregulated in the liver of patients with chronic hepatitis and fibrosis, and that WT1 can participate in the mechanisms leading to the loss of hepatocellular function. We have also demonstrated that WT1 is expressed in human HCC, and that this gene contributes to the dedifferentiationon of liver cancer cells, and to their resistance to chemotherapeutic agents. Therefore, we have uncovered a novel potential therapeutic target in liver cancer.
•    We have proposed that AR may play an intermediary function between inflammation and hepatic fibrogenesis. AR expression is induced by inflammatory signals (cytokines, LPS), and we have shown for the first time that AR may be a novel survival and proliferative factor for extracellular matrix-producing cells.
•    We have described the existence of an AR-mediated autocrine loop in human HCC. We have provided functional evidence demonstrating the relevance of this autocriny in HCC growth and survival. AR expression was found to be essential towards cell death induced by TFG- b eta and chemotherapeutics.
•    In collaboration with Dr. Fernando Corrales we have studied the molecular mechanisms implicated in the impairment of methylthioadenosine (MTA) metabolism in acute and chronic liver injury as well as in HCC. We have identified the mechanisms leading to the silencing of MTA-phosphorylase (MTAP) in cirrhosis and HCC, as well as the specific interaction of this enzyme with reactive oxygen species. We have been also interested in the study of the therapeutic potential of MTA in inflammatory diseases.