Cholesterol – the devil you know; ceramide – the devil you don’t

Ectopic lipids play a key role in numerous pathologies, including heart disease, stroke, and diabetes. Of all the lipids studied, perhaps the most well understood is cholesterol, a widely used clinical biomarker of cardiovascular disease and a target of pharmacological interventions (e.g., statins). Thousands of studies have interrogated the regulation and action of this disease-causing sterol. As a growing body of literature indicates, a new class of lipid-based therapies may be on the horizon. Ceramides are cholesterol-independent biomarkers of heart disease and diabetes in humans. Studies in rodents suggest that they are causative agents of disease, as lowering ceramides through genetic or pharmacological interventions prevents cardiovascular disease and diabetes. Herein, we discuss the evidence supporting the potential of therapeutics targeting ceramides to treat cardiometabolic disease, contrasting it with the robust datasets that drove the creation of cholesterol-lowering pharmaceuticals. Pioneering studies on cholesterol have revolutionized our understanding of the role of lipids in cardiovascular disease.The widely prescribed statins inhibit cholesterol biosynthesis to prevent coronary artery disease.By lowering liver cholesterol, statins reduce levels of circulating lipoproteins and decrease levels of numerous serum lipids (including ceramides).Like cholesterol, ceramides contribute to some of the pathologies associated with obesity, but they have a distinct spectrum of actions: they alter tissue metabolism and induce apoptosis.In rodents, blocking ceramide accumulation ameliorates a spectrum of disorders including diabetes, fatty liver disease, and heart disease.Serum ceramides correlate strongly with markers of diabetes and heart disease.Therapeutic approaches that lower ceramides could have efficacy in a broad spectrum of metabolic disorders.