Ceramides as Emerging Players in Cardiovascular Disease: Focus on Their Pathogenetic Effects and Regulation by Diet

Abstract

Impaired lipid metabolism is a pivotal driver of cardiovascular disease (CVD). In this regard, the accumulation of ceramides within the circulation as well as in metabolically active tissues and atherosclerotic plaques is a direct consequence of derailed lipid metabolism. Ceramides may be at the nexus between impaired lipid metabolism and CVD. Indeed, although on one hand ceramides have been implicated in the pathogenesis of CVD, on the other specific ceramide subspecies have also been proposed as predictors of major adverse cardiovascular events. This review will provide an updated overview of the role of ceramides in the pathogenesis of CVD, as well as their pathogenetic mechanisms of action. Furthermore, the manuscript will cover the importance of ceramides as biomarkers to predict cardiovascular events and the role of diet, both in terms of nutrients and dietary patterns, in modulating ceramide metabolism and homeostasis.

Keywords: Mediterranean diet; Western diet; atherosclerosis; cardiovascular disease; ceramide; dietary fatty acids.

FIGURE 1

Circulating ceramides and their implications in cardiovascular disease risk. Ceramides, particularly C16:0 and C18:0 long-chain ceramides, play a pivotal role in the pathogenesis of cardiovascular diseases (CVDs). Among the mechanisms underpinning their impact on CVD risk, ceramides can promote atherosclerosis by accumulating within the atherosclerotic plaque where they induce LDL-cholesterol aggregation and oxidation, thereby contributing to oxidative stress. Ceramides induce macrophage polarization toward an M1 proinflammatory phenotype via the activation of the NLRP3-inflammosome, whereas in the adipocytes they trigger the activation of the NF-kβ signaling pathway. Moreover, long-chain ceramides are implicated in the pathogenesis of obesity and type 2 diabetes, by promoting hypothalamic dysfunction and insulin resistance, respectively. Finally, high levels of circulating ceramides may increase blood pressure. GLUT4, glucose transporter-4; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3; oxLDL-cholesterol, oxidated low-density lipoprotein cholesterol; This figure was created using BioRender.com.

FIGURE 2

The impact of dietary patterns and nutrients upon circulating ceramide metabolism. Dietary patterns, as well as specific nutrients, can modulate ceramide synthesis and accumulation. The Western diet is characterized by the overconsumption of energy-dense foods rich in long-chain saturated fatty acids (LCSFAs), among which palmitic acid represents the building block for de novo synthesis of these sphingolipids. Moreover, LCSFA promotes proinflammatory responses which can foster the activation of the key enzymes involved in the synthesis of ceramides, both via the de novo and sphingomyelinase pathways. In keeping with this, LCSFA may impair mitochondrial oxidative capacity and functionality with the consequent accumulation of fatty acids which be channeled toward ceramide synthesis. Apart from palmitic acid, also fructose may promote ceramide synthesis. Contrarily to the Western diet, the Mediterranean diet, especially for its content in mono- (MUFA) and omega-3 PUFA, may reduce circulating ceramides by improving mitochondrial oxidative capacity, and metabolic flexibility and reducing systemic inflammation. Furthermore, ω-3 fatty acids, along with inulin, may improve the gut microbiota functionality and diversity as indicated and increase its richness and short-chain fatty acid production. CerS, ceramide synthase; SMase, sphingomyelinase; SPT1, serine-palmitoyl transferase-1. This figure was created using smart.servier.com and BioRender.com.