Final Activity Report Summary - HPPARA FUNCTION (Human PPARa function in the vascular system)
Animal models and, specifically, mouse models have been the most useful tool to increase our understanding of physiology. However, rodents are not humans and experiments performed in mice cannot accurately predict outcomes of a disease progression in humans. The generation of humanised mice carrying human genes and mimicking human physiological systems may help overcome these obstacles. PPAR? (peroxisome proliferator-activated receptor alpha) belongs to the nuclear receptor superfamily which is a group of cellular membrane receptors that can be activated by specific ligands. PPAR? activation is implicated in lipid metabolism, inflammation and atherosclerosis. Indeed, the use of synthetic agonists for PPAR? in clinical treatments (specifically fibric acid derivatives like fenofibrate) has demonstrated to have beneficial effects on cardiovascular disease outcome by lowering plasma lipid levels (triglycerides and cholesterol) and probably by controlling inflammation. However, no data are available concerning the relative contribution of the human PPAR? protein to atherosclerosis process.
In this project we have worked with a humanised mouse expressing the human PPAR? gene (PPAR?KI mice) to predict the physiological functions of this protein in humans. Surprisingly, PPAR?KI mice express very low levels of PPAR? ?in liver while its expression is normal in all other tissues analysed. In addition, fenofibrate treatment failed to influence plasma lipids in these mice. These data show that human PPAR? is not enough expressed in mouse liver to be functional in PPAR?KI mice and demonstrate that fenofibrate lipid lowering properties depend on hepatic PPAR? activation.
This unexpected result turned these mice into a suitable model to study the peripheral human PPAR? functions independent from the known roles of PPAR? in liver. To study these functions during atherosclerotic plaque formation, humanised mice were fed with a 'western-like' diet (lipid enriched food which induces atherosclerotic plaque formation in mice aortas) and supplemented or not with fenofibrate (to activate PPAR??. After ten weeks of diet we found that the humanised mice treated with fenofibrate developed atherosclerotic plaques to a lower extent than untreated humanised mice without any change in plasma lipid levels. Thus, we can conclude, that peripheral human PPAR? exerts anti-atherogenic actions independently of its lipid-lowering properties.
In this project we have worked with a humanised mouse expressing the human PPAR? gene (PPAR?KI mice) to predict the physiological functions of this protein in humans. Surprisingly, PPAR?KI mice express very low levels of PPAR? ?in liver while its expression is normal in all other tissues analysed. In addition, fenofibrate treatment failed to influence plasma lipids in these mice. These data show that human PPAR? is not enough expressed in mouse liver to be functional in PPAR?KI mice and demonstrate that fenofibrate lipid lowering properties depend on hepatic PPAR? activation.
This unexpected result turned these mice into a suitable model to study the peripheral human PPAR? functions independent from the known roles of PPAR? in liver. To study these functions during atherosclerotic plaque formation, humanised mice were fed with a 'western-like' diet (lipid enriched food which induces atherosclerotic plaque formation in mice aortas) and supplemented or not with fenofibrate (to activate PPAR??. After ten weeks of diet we found that the humanised mice treated with fenofibrate developed atherosclerotic plaques to a lower extent than untreated humanised mice without any change in plasma lipid levels. Thus, we can conclude, that peripheral human PPAR? exerts anti-atherogenic actions independently of its lipid-lowering properties.