Search

Alcohol-related brain injury is characterized by cognitive deficits and brain atrophy with the prefrontal cortex particularly susceptible. White matter in the human brain is lipid rich and a major target of damage from chronic alcohol abuse; yet, there is sparse information on how these lipids are affected. Here, we used untargeted lipidomics as a discovery tool to describe these changes in the prefrontal, middle temporal, and visual cortices of human subjects with alcohol use disorder and controls. Significant changes to the lipidome, predominantly in the prefrontal and visual cortices, and differences between the white and grey matter of each brain region were identified. These effects include broad decreases to phospholipids and ceramide, decreased polyunsaturated fatty acids, decreased sphingadiene backbones, and selective decreases in cholesteryl ester fatty acid chains. Our findings show that chronic alcohol abuse results in selective changes to the neurolipidome, which likely reflects both the directs effects on the brain and concurrent effects on the liver.

Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod are valuable immunosuppressants used to treat multiple sclerosis, and promote oligodendrocyte survival. However, the role for endogenous S1P, synthesized by the enzyme sphingosine kinase 2 (SphK2), in oligodendrocyte survival and myelination has not been established. This study investigated the requirement for SphK2 in oligodendrocyte survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. Oligodendrocyte density did not differ between untreated wild- type (WT) and SphK2 knockout (SphK2-/-) mice. However, cuprizone treatment caused significantly greater loss of mature oligodendrocytes in SphK2-/- compared to WT mice. Following cuprizone withdrawal, spontaneous remyelination occurred in WT but not SphK2-/- mice, even though progenitor and mature oligodendrocyte density increased in both genotypes. Levels of cytotoxic sphingosine and ceramide were higher in the corpus callosum of SphK2-/- mice, and in contrast to WT mice, did not decline following cuprizone withdrawal in SphK2-/- mice. We also observed a significant reduction in myelin thickness with ageing in SphK2-/- compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalysing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with ageing. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination.Table of Contents ImageMain PointsThe lipid kinase sphingosine kinase 2 (SphK2) is essential for remyelination following a demyelinating insult (cuprizone).SphK2 protects against cuprizone-mediated oligodendrocyte loss.SphK2 deficiency leads to thinner myelin with ageing.

The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD + STZ approach were used to generate ventricular samples (n = 9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ-aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.