IDIBAPS, Institut d'Investigacions Biomèdiques August Pi i Sunyer

Main lines of research

1. Ischemia-reperfusion liver cell damage mechanisms and their regulation based on antioxidant and antiinflammatory strategies.

2. Sphingolipid and mitochondrial oxidative stress regulation of cell death.

3. Regulation of cholesterol homeostasis in patients and experimental models of non-alcoholic steatohepatitis.

4. Mechanisms responsible for cholesterol mitochondrial transit.

5. Role of cholesterol in hepatocellular carcinoma response to chemotherapy.

6. Role of cholesterol and mitochondrial GSH in Alzheimer’s disease.

7. Contribution of acid sphingomyelinase to liver fibrosis.

Three lines in which we have obtained important results are:

1. Alterations of the mitochondrial antioxidants glutathione and S-adenosylmethionine in the development of non-alcoholic steatohepatitis (NASH). A diet deficient in methionine and choline is the typically applied animal model of non-alcoholic steatohepatitis (NASH), since it reflects the steatosis, mitochondrial dysfunction, liver cell damage, oxidative stress, inflammation and fibrosis characteristic of the human disease. Our study in the Journal of Biological Chemistry shows that methionine deficiency is specifically the cause of the decrease in mitochondrial antioxidant defense (glutathione and S-adenosylmethionine) and of the increase in mitochondrial membrane rigidity. These mitochondrial alterations favor liver cell sensitivity to “second impacts” such as the inflammatory cytokines. For this reason, therapies with permeable pro-glutathion compounds can be effective for avoiding the progression of non-alcoholic steatohepatitis.

2. Acid sphingomyelinase participates in the activation of stellate cells and in liver fibrosis. Hepatic stellate cells (HSCs) participate in the development of liver fibrosis through their trans-differentiation/activation to yield myofibroblast-type cells. Acid sphingomyelinase (ASMase) is a known sphingolipid enzyme that regulates liver cell death induced by oxidative stress and through the mediation of death receptors. Our article in the American Journal of Pathology shows that ASMase is activated during HSC activation in parallel to an increase in catepsin B and D processing. The pharmacological inhibition of ASMase or its genic silencing reduces catepsin activation and the trans-differentiation and proliferation of HSCs. In samples from patients with fibrosis induced by non-alcoholic steatohepatitis (NASH), the ASMase/catepsin axis is clearly increased compared with the situation found in healthy subjects. These results point to the importance of the ASMase/catepsin pathway in HSC activation, and suggest that their antagonism may prove relevant in the treatment of liver fibrosis.

3. Growth arrest-specific 6 (GAS6) protein induces liver protection against murine ischemia/reperfusion (I/R) damage. While GAS6 is known to promote cell growth and survival during cell repair and the development of different organs, its participation in the protection and posterior repair of liver cell damage caused by ischemia/reperfusion had not been previously explored. Our paper published in Hepatology evidences that GAS6 activates post-ischemic protection mechanisms (AKT) in the liver, and that animals deficient in this protein are highly sensitive to I/R. Moreover, recombinant GAS6 is able to protect the ischemic liver, administered to both wild-strain animals and animals deficient in this protein. Thus, GAS6 appears as a liver protective molecule and as a potential therapeutic target for increasing protection against I/R and possibly also against other hepatotoxic stimuli.