Metabolic Messengers: ceramides

Abstract

Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.

Fig. 1 |. Discovery of ceramides as metabolic messengers.

Nearly 100 years passed between the discovery of sphingolipids (1884) and the determination that sphingolipids such as ceramides have biological activities as intracellular messengers that alter cell survival and metabolism (1990s). In the mid- to late 2000s, a series of studies using pharmacological reagents (for example, myriocin) or genetically engineered mice revealed that blocking ceramide synthesis ameliorates atherosclerosis, diabetes and heart disease. Subsequently, adiponectin receptors were identified as ceramides, and the fields of research on these two metabolic messengers converged (2011–2017). As lipidomic technologies improved, large-scale lipidomic profiling studies became possible, revealing tight associations between serum and tissue ceramides and cardiometabolic disease (2014–2019). Finally, research in mice has revealed that making subtle modifications to the ceramide molecules (for example, by altering their acylation patterns or the desaturation status of the sphingoid backbone) is sufficient to ameliorate cardiometabolic disease, thus revealing new therapeutic strategies for combating these disorders (2014–2019).

Fig. 2 |. Ceramides as signals of lipid excess.

Left, simplified schematic of the ceramide-biosynthesis pathway, highlighting enzymes discussed in this review. Pharmacological inhibition or genetic depletion of SPT, CERS1, CERS6 and DES1 lowers ceramides and ameliorates insulin resistance and cardiometabolic disorders. Moreover, transgenic overexpression of ASAH1, ADIPOR1 or ADIPOR2 produces the same beneficial effects. Right, simplified schematic depicting the central hypothesis that ceramides are gauges of FFA excess. The mechanisms that ceramides invoke are as follows: (1) redistribution of CD36 toward the plasma membrane, thus facilitating the safe uptake of FFA and enhancing the conversion of fatty acids into acyl-CoA; (2) induction of Srebf1, thus stimulating the synthesis of cholesterol, a partner of ceramide and sphingomyelin in lipid rafts, and inducing genes that facilitate the conversion of FFA into inert triglycerides; (3) inhibition of Akt (PKB), which slows glucose utilization in adipose tissue and muscle, thus facilitating the usage of lipids for energy, while inhibiting hepatic gluconeogenesis; (4) inhibition of HSL, which prevents liberation of additional FFA from lipid droplest; (5) inhibition of mitochondrial complexes, thus calibrating the metabolic efficiency in situations with energy surplus; (6) repression of lipase expression by ceramide synthases. KDSR, 3-ketodihydrosphingosine reductase; ASAH1, acid ceramidase; MFF, mitochondrial fission factor.

Fig. 3 |. Target tissues and metabolic activities of ceramides.

Ceramides influence cardiometabolic disease in mice and humans. Most observations have been conclusively demonstrated in rodents and are supported by strong correlational data from humans. The physiological effects of ceramide are therefore strongly preserved between the two organisms. Ceramide effects include induction of insulin resistance, impairment in vascular reactivity, enhancement of triglyceride synthesis, impairment in lipid oxidation, inhibition of insulin gene transcription and stimulation of apoptosis and fibrosis.