Sphingolipid Profiling: A Promising Tool for Stratifying the Metabolic Syndrome-Associated Risk

Abstract

Metabolic syndrome (MetS) is a multicomponent risk condition that reflects the clustering of individual cardiometabolic risk factors related to abdominal obesity and insulin resistance. MetS increases the risk for cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM). However, there still is not total clinical consensus about the definition of MetS, and its pathophysiology seems to be heterogeneous. Moreover, it remains unclear whether MetS is a single syndrome or a set of diverse clinical conditions conferring different metabolic and cardiovascular risks. Indeed, traditional biomarkers alone do not explain well such heterogeneity or the risk of associated diseases. There is thus a need to identify additional biomarkers that may contribute to a better understanding of MetS, along with more accurate prognosis of its various chronic disease risks. To fulfill this need, omics technologies may offer new insights into associations between sphingolipids and cardiometabolic diseases. Particularly, ceramides -the most widely studied sphingolipid class- have been shown to play a causative role in both T2DM and CVD. However, the involvement of simple glycosphingolipids remains controversial. This review focuses on the current understanding of MetS heterogeneity and discuss recent findings to address how sphingolipid profiling can be applied to better characterize MetS-associated risks.

Keywords: cardiovascular risk (CVD); ceramides; metabolic syndrome; sphingolipids; type 2 diabetes.

Figure 1

Sphingolipid metabolic pathway. SPLs have three major metabolic pathways, all of which converge into ceramides: (a) de novo synthesis coming from saturated fatty acids, (b) breakdown pathway in which sphingomyelin loses its phosphocholine headgroup, and (c) salvage pathway that allows sphingosine recycling from complex SPLs. The fatty acid (light orange box) defines SPL species, whereas the headgroup (dark orange boxes) defines the SPL class.

Figure 2

Possible impact of blood sphingolipid profile on MetS-associated cardiovascular vs. metabolic risk based on cross-sectional and longitudinal association studies. Abbreviations are as follows: metabolic syndrome (MetS), atherosclerotic cardiovascular disease (ASCVD), and type 2 diabetes mellitus (T2DM). The “plus sign” denotes a positive association between the respective disease progression and the sphingolipid class, while the minus sign denotes a negative association.