Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Irina Alecu,Alaa Othman,Anke Penno,Essa M Saied,Christoph Arenz,Arnold Von Eckardstein,Thorsten Hornemann

doi:10.1194/jlr.m072421

Abstract

The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.

Highlights

Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) [1,2,3]
We demonstrated for the first time that 1-deoxySO is metabolized to a variety of downstream metabolites through reactions that are at least partly mediated by enzymes of the cytochrome P450 (CYP)4F subfamily
Current belief holds that 1-deoxySLs are metabolic “dead-end” products that cannot be degraded by the canonical SL catabolic pathway due to their missing C1 hydroxyl group

Summary

Introduction

Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) [1,2,3]. Plasma 1-deoxySLs are elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D [6] and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 [7, 8]. Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers [9, 10]. Elevated 1-deoxySL plasma levels are predictive for the risk to develop T2D [6]

Methods

Results

Conclusion