Grant: Project Grant

Heart failure (HF), a major cause of mortality, is a disease characterized by the incapacity of the heart to effectively contract. Fatty liver is associated with obesity but also occurs in lean people. "Lipidomics" is a method that scans the lipids (fat), referred to as the "lipidome", of our body. It allows to identify markers of fatty liver disease to better understand its progression to heart manifestations. We recently observed various changes in the blood and cardiac lipidome of mice with fatty livers that included, among other, decreased plasmalogen lipids. However, the progressive lipids changes and the role of decreased plasmalogens in cardiac manifestation of fatty liver, is ill defined. We also observed an association with decreased cardiolipin lipids that are key components of the "energetic central of all cells", called the mitochondrion, and markers of mitochondrial function were altered in these mice. We hypothesise that the characterization of the changes in the lipidome will allow us to anticipate the heart effects of the fatty liver disease and identify novel mechanisms whereby this disease leads to reduced heart function. Among changes in the lipidome, reduced plasmalogen levels may affect lipid composition of cardiac cells, leading to functional impairment of the mitochondria in these cells, and eventually reduced cell survival. Hence, our objectives are to determine the effects of fatty liver disease, but also decreased plasmalogens, on both heart and mitochondrial function. These studies will use a combination of murine and cellular models to address the following questions: i) what are the cardiac manifestation of a genetic mouse model of mitochondrial liver disease without obesity? ii) what are the changes in the lipidome over time with changes in heart function in a mouse model of obesity? iii) how plasmalogens affect cellular and mitochondrial function, and how we can rescue it, using an experimental cardiac cell deficient in plasmalogens?