Endonuclease V - A new target in metabolic syndrome

Along with obesity often come high blood pressure, high blood glucose and triglycerides as well as accumulation of fat in the blood vessels. Hence, overweight is a risk factor for developing diabetes and coronary heart disease and represents a serious challenge for authorities and health care systems. A better understanding of the pathology behind is a prerequisite for better handling and proper actions. We have interest in Endonuclease V (EndoV) which is an enzyme with specificity for certain RNAs acting by cleaving them in two. The biological significance of this cleavage is unknown, but EndoV appears especially important for certain immune cells like monocytes and macrophages. Our data do not support a function of EndoV in general RNA decay, but rather in fine tuning the levels of specific RNAs under stress. Mice that lack this enzyme are viable, but have sign of metabolic dysfunction. It was therefore rather surprising that EndoV-/- mice were less atherosclerotic than control mice. Macrophage infiltration was decreased in the EndoV-/- mice which could be the direct reason for the reduced plaque burden. It is well documented that macrophages play key roles in atherosclerosis development. Also in another disease model in mice; liver cancer, animals without EndoV managed better as they develop fewer and smaller tumors. The liver is central for normal metabolism where again, macrophages plays vital roles. We analyzed patient materials for EndoV gene expression and found aberrant regulation both in carotic plaques and fatty livers (which may progress into liver cancer) compared to health tissue, suggesting involvement of EndoV also in humane disease. More experiments are needed to understand mechanisms behind, what kind of stress is important and also how it is possible to achieve "beneficial" health effects by deleting a gene.

Impact of results. The project has generated new knowledge on an enzyme, Endonuclease V, that until this project was poorly described. We have found important role in the progression of two different diseases in mice; atherosclerosis and liver cancer. Both disease are common in man, and our results strongly indicate involvement of EndoV also here. If our findings are confirmed in human studies, there is a therapeutic potential. Our results opens up for further studies both locally, interdisciplinary and internationally. Long term beneficial societal effects at this stage of the project can not be assigned.

Obesity is often followed by metabolic syndrome with a clear link to diabetes, hepatic and cardiovascular disease. Affection of the liver is manifested as accumulation of fat followed by inflammation which may advance into fibrosis, liver failure and/or hepatocellular carcinoma. Risk factors for fatty liver are diet and inactivity whereas genetic contribution is ~25%. A few genes are found important and based on recent observation in our laboratory we suggest adding EndoV (endonuclease V) to this list. Mice that lack EndoV develop several signs of metabolic syndrome with increased glucose intolerance and body weight as well as fatty liver. EndoV homologs are found in all domains of life and constitute a family of highly conserved proteins. Bacterial EndoVs are DNA repair enzymes for deaminated adenosine (inosine=I), however, the mammalian counterparts rather act at inosines in RNA. Whereas inosine in DNA is unwanted, inosines are enzymatically introduced in RNA by adenosine deaminases (ADAR) to increase transcriptome diversity (inosine behaves as guanosine). This editing is essential for normal development and health in mammals underscoring its importance. ADARs are well characterized enzymes with expression patterns that are dynamically regulated. How the level of edited transcripts is maintained is poorly understood, but EndoV could be involved by selective removal of I-containing transcripts. To unravel the biological significance of the RNA-incision activity of EndoV, transgenic mice were generated. Inspection revealed metabolic- and liver affection in these mice. The major goal for this project is to elucidate molecular mechanism leading to metabolic disturbances in EndoV-/- mice and to relate this to similar conditions in humans. By the combined use of molecular- and cell biology techniques as well as transgenic mice and patient material, we aim to define the role of EndoV in development and progression of metabolic syndrome in mammals.