Ceramides in Metabolism: Key Lipotoxic Players

Abstract

The global prevalence of metabolic diseases such as type 2 diabetes mellitus, steatohepatitis, myocardial infarction, and stroke has increased dramatically over the past two decades. These obesity-fueled disorders result, in part, from the aberrant accumulation of harmful lipid metabolites in tissues not suited for lipid storage (e.g., the liver, vasculature, heart, and pancreatic beta-cells). Among the numerous lipid subtypes that accumulate, sphingolipids such as ceramides are particularly impactful, as they elicit the selective insulin resistance, dyslipidemia, and ultimately cell death that underlie nearly all metabolic disorders. This review summarizes recent findings on the regulatory pathways controlling ceramide production, the molecular mechanisms linking the lipids to these discrete pathogenic events, and exciting attempts to develop therapeutics to reduce ceramide levels to combat metabolic disease.

Keywords: atherosclerosis; ceramides; diabetes; dyslipidemia; insulin resistance; obesity.

Figure 1

De novo ceramide synthesis pathway and known inhibitors shown to improve metabolic diseases. Schematic of the de novo ceramide biosynthesis pathway highlighting the key enzymes involved in ceramide biosynthesis and their respective inhibitors. Abbreviations: ASAH1, acid ceramidase; CERS, ceramide synthase; DES, dihydroceramide desaturase; KDSR, 3-ketodihydrosphingosine reductase; SPT, serine palmitoyltransferase; UGCG, UDP-glucose ceramide glucosyltransferase.

Figure 2

Molecular mechanisms via which ceramides gauge intracellular lipids. Ceramides regulate metabolism through the following mechanisms: translocation of CD36 toward the plasma membrane, thus facilitating the safe uptake of FFA and enhancing the conversion of fatty acids into acyl-CoA, induction of Srebf1, inhibition of Akt/PKB, inhibition of HSL, safe storage of ceramide as 1-O-acylceramide inhibition of mitochondrial metabolic efficiency, and inhibition of lipases. Abbreviations: Akt/PKB, protein kinase B; CD36, cluster of differentiation 36; CERS, ceramide synthase; DES1, dihydroceramide desaturase 1; FFA, free fatty acid; HSL, hormone-sensitive lipase; PKCζ, protein kinase zeta; PP2A, protein phosphatase 2A; SPT, serine palmitoyl transferase; Srebf1, sterol regulatory element-binding protein 1.

Figure 3

Key regulators of ceramide accumulation. Depicted are the key regulators of ceramide synthesis thus far identified and involved in metabolic diseases.