Sphingolipids along with sterols and glycerophospholipids are the building blocks for cellular membranes. In our research, we focus on the various aspects of ceramide and sphingolipid metabolism. The cellular synthesis of sphingolipids starts with the condensation of an activated fatty acid, typically palmitoyl-CoA and the amino acid L-serine. This reaction is catalyzed by the enzyme serine palmitoyltransferase (SPT). In addition to canonical substrates, SPT can also metabolize other fatty acids with a chain length from C12 to C18 and – under certain conditions – also the amino acids L-alanine and glycine. This results in a series of atypical sphingolipid metabolites. Particularly, the conjugation of alanine and glycine leads to the formation of a new class of 1-deoxy-sphingolipids. Due to the altered chemical structure, these 1-deoxy-sphingolipids cannot be metabolized by the regular catabolic degradation pathway. Various mutations in SPT are associated with a pathological increase in 1-deoxy-sphingolipids. This results in damage to the peripheral nerves, which manifests itself clinically in the progressive loss of sensory perception (sensation of pressure, temperature and pain) and peripheral neuropathy (hereditary sensory and autonomic neuropathy type 1 – HSAN1).
Metabolically, SPT connects two separate metabolic pathways (metabolism of fatty acids and amino acids), which in turn are indirectly connected to carbohydrate metabolism. Therefore, chronic metabolic changes manifest themselves in an altered spectrum of sphingolipids in the blood. In clinical studies, we have shown that the spectrum of atypical sphingolipid metabolites in blood is significantly different in metabolic disorders, such as the metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and atherosclerosis. In particular, in individuals suffering from MetS or T2DM, the concentration of 1-deoxy-sphingolipids is significantly increased and may play a role in the pathogenesis of insulin resistance, beta-cell failure and diabetic sensory neuropathy. Current findings also reveal that certain sphingolipid metabolites are prognostic and clinically relevant biomarkers that help to estimate the risk of metabolic disorders and facilitate the monitoring of drug therapy. As part of our research, we want to gain a better understanding of the role of sphingolipids in pathological changes and as a clinical biomarker.
Prof. Thorsten Hornemann (assistant professor)
Gergely Karsai (doctoral candidate)
Dr. Museer Ahmad Lone (postdoc)
Regula Steiner (doctoral candidate)
Saranya Suriyanarayanan (doctoral candidate)
Yu Wei (biomedical scientist)
University Hospital Zurich
Institute of Clinical Chemistry
Prof. Thorsten Hornemann