Hepatocyte-specific loss of manganese superoxide dismutase causes liver failure

In the mitochondrial matrix manganese superoxide dismutase (MnSOD) is the essential antioxidant enzyme that converts O₂ ^●- to H₂O₂ which can then be converted to water by glutathione peroxidase. The liver has the highest specific MnSOD activity, which implies its important role for maintaining proper organ function and to prevent pathological situations such as cancer. In line with this, it was proposed that the MnSOD gene may act as a tumor suppressor gene. However, the exact molecular mechanism by which this antioxidant enzyme suppresses the malignant cellular phenotype has not yet been elucidated. Therefore, it is the aim of the current proposal to study the role of MnSOD in the liver of mice with hepatocyte-specific MnSOD deficieny and to identify molecules critically involved in MnSOD-dependent pathologies.

To do this we generated hepatocyte-specific knockout mice with the Cre/loxP system by crossing mice expressing Cre recombinase under the control of the a-fetoprotein promoter with mice in which exon three of the MnSOD gene is flanked by two loxP sites. After intercrossing, hepatocytes expressing the recombinase in the double transgenic offspring delete the conditional allele, while the target gene remains intact in all other tissues where the recombinase is not expressed. We found that livers of mice were reduced in size and contained inflammatory foci, an enhanced number of nodule forming ductular proliferating and mitotic cells as well as a high number of apoptotic cells. Serum levels of enzymes indicating liver damage such as glutamate oxalacetate aminotransferase, glutamate pyruvate aminotransferase, cholinesterase, gamma glutamyltransferase, alkaline phosphatase were elevated compared to the control animals. In addition, bilirubin and albumin levels were also enhanced. Further, by using DNA-microarray analysis we identified 25 genes which were transcriptionally deregulated by the lack of MnSOD.

Thus, our data indcate that an intact mitochondrial MnSOD is crucial for hepatocyte integrity and liver function.

Key words

MnSOD - hepatocytes - liver faiulure