Lipidomics in translational research and the clinical significance of lipid-based biomarkers

Abstract

Lipidomics is a rapidly developing field of study that focuses on the identification and quantitation of various lipid species in the lipidome. Lipidomics has now emerged in the forefront of scientific research due to the importance of lipids in metabolism, cancer, and disease. Using both targeted and untargeted mass spectrometry as a tool for analysis, progress in the field has rapidly progressed in the last decade. Having the ability to assess these small molecules in vivo has led to better understanding of several lipid-driven mechanisms and the identification of lipid-based biomarkers in neurodegenerative disease, cancer, sepsis, wound healing, and pre-eclampsia. Biomarker identification and mechanistic understanding of specific lipid pathways linked to a disease's pathologies can form the foundation in the development of novel therapeutics in hopes of curing human disease.

Figure 1. The new scientific dogma of biological systems

The new scientific dogma for biological systems is DNA -> RNA -> Protein -> Lipids -> Phenome demonstrating that lipids are the most amenable biomolecule for biomarkers of human disease. UPLC-MS/MS is more commonly being used to determine novel lipid biomarkers in human disease and illness by observing lipid variance through the progression of disease states.

Figure 2. The Eight Classes of Lipids

Structural examples from the eight classes of lipids (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, prenol lipids, sterol lipids, saccharolipids, and polyketides). Subclasses and examples are displayed to the right of each structure.

Figure 3. The Biosynthetic Pathways for Eicosanoids and Specialized Pro-Resolution Lipid Mediators (SPM)

The C1P/cPLA₂α interaction at cellular membranes releases sn₂ bound unsaturated fatty acids (AA, EPA, DHA) from membrane-bound phospholipids. Through interactions with cyclooxygenases, cytochrome P450, or lipoxygenases; AA, DHA, and EPA are converted into pro-inflammatory (red) or anti-inflammatory (green) lipid mediators.

Figure 4. Subclasses and Structures of Glycerophospholipids

Structures are depicted for the glycerophospholipids; phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerols (PG), cardiolipins (CL), and phosphatidic acid (PA).

Figure 5. Sepsis patients differ significantly in their lipid profiles depending on outcome

In a small preliminary study, lipids were extracted from the plasma of 12 sepsis patients transferred to pulmonary ICU. This lipid extract was interrogated by targeted lipidomic analysis for bioactive lipids followed by Partial Least Squares Discriminant Analysis (PLS-DA). The resultant scores plot demonstrated clear separation between groups (shaded area = 95% confidence interval); groups were either < 5 days in the ICU or > 5 days in the ICU. The corresponding loadings plot identified the top lipids that contributed to the separation based on time the patient spent in the ICU. Of note, increased levels of phosphatidylcholine (20:4 fatty acyl in the sn₂ position) and decreased levels of lysophosphatidylcholine in the >5 days in the ICU group were the main contributing lipids.

Figure 6. The sphingolipid biosynthetic pathway

An overview of the sphingolipid biosynthetic pathway is depicted. In the de novo biosynthesis of ceramide, serine and palmitoyl-CoA are initially condensed by serine-palmitoyl transferase followed by three additional enzymatic steps involving a reductase, synthase, and desaturase respectively. Ceramide, thus produced, can be further metabolized to ceramide-1-phosphate via ceramide kinase, sphingomyelin via sphingomyelin synthases, and sphingosine via ceramidases. Sphingosine can be further converted to sphingosine-1-phosphate by the action of sphingosine kinases.