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Human lipid metabolism is extremely complex, fundamental for normal human development, and crucial for normal functioning of all different tissues of the body. Lipids play an important role in many mechanisms underlying human disease and are important drug targets. Only the development of novel biochemical techniques will lead to further understanding of this intriguing part of metabolism, and the study of rare disorders may contribute to these growing insights.
Sjögren-Larsson syndrome (SLS) is an early-onset neurometabolic disorder of brain, eye and skin, and is diagnosed in circa 1 patient every 2 years in the Netherlands. SLS is caused by deficiency of the enzyme fatty aldehyde dehydrogenase (FALDH), leading to the accumulation of long-chain fatty alcohols and aldehydes.
Research groups from Radboudumc and Amsterdam UMC have a long-standing collaboration on the clinical, genetic, and biochemical studies of SLS (Radboud University: thesis Willemsen 2001, Fuijkschot 2015, Staps 2021), but limits to technical possibilities have so far greatly hampered the understanding of the different metabolic pathways involved in SLS, and thus the development of a rational therapy targeting the disease mechanism. The researchers now studied plasma (n=12) and brain tissue (n=1) of patients with SLS, applying a novel technique called lipidomics and a newly developed bioinformatics tool, which enabled the comprehensive analysis of all lipids (the so-called lipidome) in these samples.
Besides demonstrating already known disturbances in lipid metabolism, analysis of plasma and brain tissue uncovered two new groups of endogenous lipids highly elevated in SLS compared to controls. The first group were alkylphosphocholines (APCs) and alkylphosphoethanolamines (APEs) containing different lengths of alkyl-chains. The second group was a set of 5 features of unknown structure, in which further studies suggested that they are ubiquinol-containing metabolites.
The two groups of novel plasma biomarkers appear to be ideally suited for diagnosis and follow-up of patients with SLS, and further studies of these lipids may lead to more insights into SLS pathophysiology and identification of potential therapeutic targets. The observation that APC and APE species were also found as endogenous metabolites in controls is very surprising since APCs are only known as exogenous lipids (e.g. anti-leishmaniasis and anti-cancer agents) while APEs are completely unknown in the human context. Unanticipatedly, this study has thus led to the identification of two new novel endogenous lipid classes so far unknown in humans.
Publication
Vaz FM, Staps P, van Klinken JB, van Lenthe H, Vervaart M, Wanders RJA, Pras-Raves ML, van Weeghel M, Salomons GS, Ferdinandusse S, Wevers RA, Willemsen MAAP. Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jan 3;1869(2):159447. doi: 10.1016/j.bbalip.2023.159447. Epub ahead of print. PMID: 38181883.
