LIPOLYSIS IN CARDIAC LIPID DYNAMICS AND METABOLIC SIGNALING

Heart failure is a serious condition in which the heart gradually becomes weaker and can no longer efficiently pump blood. Worldwide, an estimated 64 million people are affected by heart disease. The adult heart normally has a remarkable ability to use different types of nutrients for energy, albeit fatty acids (FAs) are the primary fuel source in the adult heart. FAs can be stored in the form of triacylglycerol (TAG) within fat cells but also in other cell types including heart muscle cells. Cellular TG deposits can be hydrolyzed to release FAs not only as energy fuel but also as intermediates for the synthesis of other lipids like membrane lipids, where phospholipids are the dominant lipid species. Adipose Triglyceride Lipase (ATGL) is an enzyme that starts the process of breaking down stored TAG or fat inside our cells. This process, called lipolysis, turns large fat molecules into smaller ones thereby delivering FAs that the body can use for energy. Previous studies demonstrate an important role of ATGL in TG catabolism in adipose tissue and non-adipose tissues including cardiac muscle. ATGL deficiency in mice leads to marked TG accumulation in cardiac muscle and the development of lethal heart dysfunction. Humans lacking ATGL similarly develop severe heart dysfunction known as neutral lipid storage disease with myopathy. Depending on the type of mutation, a complete loss of ATGL function can cause severe heart problems, requiring heart transplantation as early as around 20 years of age. Currently, no efficient therapy for these patients is available. We have recently shown that marked cardiac fat accumulation in transgenic mice with increased cardiac expression of a fat-droplet-associated protein is compatible with normal heart function and life-span despite lowered TG catabolism. These findings suggested currently unknown changes in heart lipid and energy metabolism provoking lethal heart dysfunction in ATGL deficiency beyond fat accumulation. Preliminary data revealed changes in the lipid FA composition in the heart of ATGL-deficient mice. We hypothesize that the lack of ATGL interferes with the FA composition of membrane lipids, which plays an important role in numerous cellular functions and the accessibility to lipid damage. Moreover, we hypothesize that ATGL deficiency hinders cardiac cells to efficiently switch to the use of other energy substrates including carbohydrates and amino acids. In this project we will investigate how TG hydrolysis interferes with the composition of membrane lipids in the heart. We will study metabolites and changes in cellular proteins that may interfere with heart membrane lipid composition, metabolic flexibility and cellular energy production in ATGL deficiency. Finally, we will investigate whether increasing cardiac TG catabolism can be a therapeutic strategy to protect the heart from diet-induced metabolic disease.