Cardiac lipids and their role for cardiomyocyte function

The molecular mechanisms that drive the progression of heart failure are poorly understood due to the complex and multifactorial nature of the disease.

Previous studies have shown that the diseased heart is associated with intracellular metabolic abnormalities, including rearrangements of cardiac lipid composition (membrane sphingolipids as well as neutral lipids in droplets), which may play a causative role in disease progression.During a 4-year project, we will use a translational approach to determine the importance of cardiac lipid content and dynamics for cardiomyocyte function.

In aim 1, we will clarify the molecular mechanisms that underlie how glycosphingolipids regulate cardiomyocyte contractility and function.

Furthermore, we will use human samples to investigate whether genetic variants of sphingolipid synthesizing enzymes may predispose to and correlate with severity of cardiac dysfunction.

In Aim 2, we will identify novel mediators regulating the switch between adaptive and maladaptive lipid droplet storage.

We have identified the lipid droplet protein perilipin 5 (Plin5) to be one such mediator, and we will elucidate the mechanisms underlying the cardioprotective effects of Plin5.We anticipate that modulation of cardiac lipids represents a promising therapeutic approach, and our long-term goal is to translate our results back to humans by developing novel treatment strategies.