Title of project

Genetic Determinants of Hyperceramidemia

Abstract

Ceramides are products of fat and protein metabolism that accumulate in individuals with obesity or dyslipidemia. They serve as signals of nutrient overload, altering cellular metabolism by inhibiting glucose utilization, enhancing triglyceride synthesis, altering mitochondrial bioenergetics, and ultimately triggering apoptosis/fibrosis. These actions, when prolonged, elicit the tissue dysfunction that underlies diabetes, steatohepatitis, heart failure, and kidney disease. Indeed, these molecules are now being measured clinically, owing to their utility as prognostic indicators of major adverse cardiac events. Moreover, drug devlopment efforts are underway to identify ceramide-lowering therapeutics to prevent or reverse the diverse diseases associated with aberrant ceramide accumulation.

We aim to initiate a new collaboration with Dr. Ruth Loos of the Novo Nordisk Foundation Center for Basic Metabolic Research to identify families with inheritable gene variants that promote ceramide accumulation and increase susceptibility to cardiometabolic disease. The work will leverage unique resources such as the UK Biobank and other clinical cohorts, which will enable integrative assessments of genomes, lipidomes, and clinical outcomes. We will use this information to identify at risk individuals and learn about the regulatory mechanisms that control ceramide synthesis, metabolism and trafficking.

Ultimately this work could lay the foundation for interventions targeting ceramides and support new standard-of-care diagnostics for detecting and treating the most prevalent, costly, and deadly diseases in Denmark and the world.