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Lipidomics Analysis of Ceramides: Applications in Disease Diagnosis and Prognosis

Ceramide (Cer) is a type of sphingolipid compound composed of a long-chain fatty acid and sphingosine linked by an amide bond. It plays a critical role in maintaining cellular homeostasis and regulating various cellular processes such as growth, proliferation, differentiation, apoptosis, and damage response. As a recognized second messenger, Ceramide is implicated in the pathogenesis of various diseases and serves as a significant biomarker in disease diagnosis and prognosis.

Lipidomics analysis is a powerful analytical technique that enables researchers to study the intricate landscape of ceramides with high sensitivity and specificity. By utilizing targeted lipidomics, hundreds of lipid species can be precisely measured in a given biological sample, providing valuable insights into the roles of ceramides in various physiological and pathological processes. This technique has been widely applied in neurodegenerative disease research, where alterations in ceramide levels have been linked to disease pathogenesis. The identification and quantification of even trace amounts of ceramides with lipidomics analysis allows for a more comprehensive understanding of their biological functions. Overall, the application of lipidomics analysis in ceramide research shows great promise in the development of novel diagnostic and therapeutic strategies for neurological disorders.

Case 1 Ceramide analysis for cardiovascular diseases ⁽¹⁾

Different types of ceramides have been shown to predict the risk of cardiovascular disease (CVD) events, especially the risk of death. At the same time, phospholipids are also associated with CVD risk. Therefore, the authors analyzed whether the combination of ceramides (Cer) and phosphatidylcholines (PCs) could synergistically predict CVD events in coronary artery disease patients by studying three independent cohorts.

The authors used liquid chromatography-mass spectrometry (LC-MS) to detect and analyze the levels of ceramides and PCs in the three cohorts, which were WECAC (N=3789), LIPID trial (N=5991), and KAROLA (N=1023). A simple risk scoring system was developed in the WECAC study and validated in the other two cohorts, confirming its significant effectiveness in predicting CVD mortality, with a multivariable hazard ratio/standard deviation value of 1.44 in the WECAC cohort, and 1.47 and 1.69 in the LIPID trial and KAROLA cohorts, respectively.

The ceramide-phospholipid risk score was comparable and synergistic with previously published CVD risk models in secondary prevention. Therefore, a simple risk scoring system based on ceramides and phospholipids can effectively predict the risk of CVD events in coronary artery disease patients.

Distinct ceramide and phosphatidylcholine lipids were used in the derivation of a novel risk score (CERT2) that determines the risk for cardiovascular events and death.

Case 2 Ceramide analysis for psychiatric disorders ⁽²⁾

Major depression (MD) and bipolar disorder (BD) are often associated with increased risk of obesity and metabolic disorders, and changes in sphingolipid metabolism may be related to the pathogenesis of MD and BD.

The authors performed non-targeted and targeted lipid profiling on plasma samples from 67 patients with unipolar and bipolar affective disorders and 405 healthy controls, and found significantly elevated plasma ceramide levels and their glycated metabolites in the patient group compared to controls, especially in male patients. They also found that long-chain ceramides were more strongly correlated with age in the patient group, and plasma levels of diacylglycerol and triacylglycerol were higher. Patients receiving antidepressant medication had higher ceramide levels than those not taking these medications, and drug trials showed that, except for olanzapine, other antipsychotic drugs did not show the same correlation.

These data suggest that plasma ceramide levels are higher in patients with major depression and bipolar disorder, which increases their metabolic burden, and this effect may be further exacerbated by certain medications.

Case 3 Ceramide analysis for metabolic diseases ⁽³⁾

Sphingolipids (SP) including ceramides, sphingomyelins, and sphingosines are associated with various metabolic disorders such as obesity and type 2 diabetes (T2DM). Therefore, the disruption of SP plasma concentrations is likely to be related to these diseases, and identifying these associations can help reveal biomarkers for related diseases or a deeper understanding of the disease process.

Correlations between SPs and key clinical characteristics.

The authors conducted a lipidomics analysis of SP in the plasma of 2302 ethnic Chinese Singaporeans, compared SP results with clinical and biochemical characteristics, and followed up the participants for 11 years. They found that ceramides were positively correlated with BMI and insulin resistance assessed by the homeostatic model assessment (HOMA-IR), while hexosylceramides were negatively correlated. In addition, SP with a d16:1 sphingoid backbone had a higher correlation with BMI and HOMA-IR, while d18:2 SP had a weaker correlation.

The authors identified a significant association between SP and obesity/T2DM features, and the balance of SP metabolism was related to the pathology of obesity. Furthermore, they identified SP as a prognostic biomarker for T2DM.

References

Hilvo, Mika, et al. "Development and validation of a ceramide-and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients." European heart journal 41.3 (2020): 371-380.
Brunkhorst-Kanaan, Nathalie, et al. "Targeted lipidomics reveal derangement of ceramides in major depression and bipolar disorder." Metabolism 95 (2019): 65-76.
Chew, Wee Siong, et al. "Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence." JCI insight 4.13 (2019).

* For Research Use Only. Not for use in diagnostic procedures.

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