Metabolomics meets lipidomics: Assessing the small molecule component of metabolism

Significance 

Since the emergence of the metabolomics and lipidomics disciplines, the advancing analytical technologies have greatly driven the field to essentially all biological and biomedical areas. The application of metabolomic approaches has led scientists to identify new signaling molecules, reveal the underlying mechanisms responsible for patho(physio)logical conditions, discover potential biomarkers for early diagnosis and prognosis of diseases, screen drug targets and/or test drug efficacy, and advance personalized medicine.

Metabolomics, englobing various types of small molecule metabolite analysis (from untargeted to targeted and isotopic profiling), can be classified as a quantitative biology approach to assess the energy flow through metabolism and flow of information through metabolic signaling. Major advancements in measurement technologies, computing power and bioinformatic solutions made it possible to measure metabolites involved in energy production and storage as well as low abundant metabolites that are present in trace amounts and are responsible for the flow of information through chemical signaling. These signaling molecules provide additional information about the regulation of principal biological processes like cell growth, differentiation and activation, cell proliferation and cell death. There is ample evidence on how metabolites act as signaling molecules and regulate the activities of proteins, RNA metabolism and gene expression. This suggests that there is much to explore in the role of metabolites and their capacity to modulate the health outcomes and/or disease phenotypes.

In a new article published in the Journal BioEssays, Dr. Hector Gallart-Ayala, Dr. Tony Teav and Dr. Julijana Ivanisevic all from the Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne in Switzerland provided an expert opinion and critical review on the field of metabolomics, its origins, its role in the postgenomic era of biochemistry and its application in investigating the role and activity of metabolites and to provide new strategies for the regulation of metabolic processes and health outcomes. The Swiss researchers believe that the characterization and investigation of metabolic profiles using metabolomic approaches will pave the way to a new era in diagnosing and treating diseases.

The metabolome is a small molecule complement (<1500 Da) of a cell, tissue or a biofluid. It is composed of polar metabolites such as sugars, carbohydrates, amino acids and their derivatives, and lipids and lipid-like metabolites. These primary metabolites play an important role in organismal survival as they serve as building blocks of structural components of cells, fuels for cellular energetics, and (bio)active and signaling molecules. In addition to genes and their function that were in the spotlight during the past era of biochemical genetics, metabolomics, including lipidomics, is bringing back the focus of metabolism research to metabolites. “Metabolomics allows us to investigate metabolism directly by analyzing metabolites instead of postulating the outcomes from gene and protein perspective.”  said Dr. Julijana Ivanisevic.

At the molecular level, the metabolic profile is a dynamic and sensitive measure of phenotype. It unites the response to environmental exposures and metabolic capacity defined by genes. “Metabolomics has become a tool of choice for understanding how the exposome impacts biological responses and therefore human health.” said Dr. Tony Teav. Mass spectrometry based techniques continue to evolve at a constant pace resulting in an expansion in the coverage of the polar and lipid metabolome and providing the accuracy and precision for its quantification. These continuous technological improvements have propelled the analysis of the metabolites to expand from the ability to measure metabolites that are highly abundant and involved in energy production and storage, towards the measurement of low abundant signaling metabolites involved in the metabolic signaling and regulation. The development of high-throughput quantitative methods, and their combination with experimental biological approaches has provided researchers the opportunity to revisit the metabolism, from model systems to human populations. Instead of reducing metabolites to biomarkers, new insights have been gained on the far-reaching role and (bio)activity of metabolites in relation to mechanisms underlying complex metabolic diseases (from obesity and diabetes to cardiovascular and neurodegenerative diseases).

“Recent technological advancements expanded the metabolite analyses to an ‘omics scale and therefore allowed for the integration of metabolic profiles in genome-wide association studies, as intermediary phenotypes, providing a link between gene variants and complex clinical end-points (i.e. extremely heterogeneous disease states).” Dr. Julijana Ivanisevic, corresponding author told Medicine Innovates. Quantitative data is currently being generated on the concentrations of metabolites across clinically well characterized and genotyped human population(s). This will help to advance the hypothesis on molecular mechanisms behind complex metabolic traits and data interpretation in the physiologically relevant context of body cycles, and energy homeostasis regulation. The scientific report on deregulated metabolic pathways is important in understanding the health outcome and pathophysiological processes and eventually help in the control of metabolic disease phenotype. The untargeted approach is no doubt a valuable discovery approach, but the isotopic profiling and targeted quantification must become an essential aspect of metabolomic studies to produce the most conclusive and cross-comparable data and aid the interpretation in a context that is biologically relevant.

In a statement to Medicine Innovates, first author Dr. Hector Gallart-Ayala said: “New improvements in quantitative metabolomics/lipidomics together with standardization initiatives will bring metabolomics to the next level” . In a nutshell with the current outbreak of metabolic diseases such as cancer, neurodegenerative diseases and cardiometabolic disorders, indeed, with advancements in the human metabolome research, we can advance the accurate diagnosis and treatment of many diseases.

Metabolomics meets lipidomics: Assessing the small molecule component of metabolism - Medicine InnovatesFigure 1. Longitudinal population monitoring combining clinical phenotyping, genotyping and metabotyping, for improved health risk assessment and personalized health care.

 

Metabolomics meets lipidomics: Assessing the small molecule component of metabolism - Medicine InnovatesFigure 2. Metabolic profiling from model systems to human population studies. Due to its high-throughput and phenotyping capacity, metabolomic / lipidomic approaches, from untargeted screening to targeted quantification and isotopic profiling, can be applied from different model systems to clinical research studies.

 

Reference

Gallart-Ayala H, Teav T, Ivanisevic J. Metabolomics meets lipidomics: Assessing the small molecule component of metabolism. Bioessays. 2020;42(12):e2000052.

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