title: Differential regulation of sphingolipid metabolism in plasma, hippocampus, and cerebral cortex of mice administered sphingolipid modulating agents.
abstract: Accumulation of ceramide is implicated in mediating the cellular responses to stress and aberrant sphingolipid metabolism is frequently associated with metabolic and neurodegenerative diseases. It is often assumed that (i) peripheral disturbances in sphingolipid concentrations are reflective of processes occurring in the brain, or (ii) circulating sphingolipids directly influence cerebral sphingolipid abundance. In order to address these assumptions, this study explores, in a physiological system, the metabolic pathways regulating sphingolipid metabolism in the brain and plasma of mice. Male C57Bl/6 were maintained on a low fat (control diet) or saturated fat enriched (SFA) diet with, or without the provision of sphingolipid modulating agents. Following 6 months of feeding, the abundance of seven sphingolipid classes was assessed by LC-ESI-MS/MS in the hippocampus (HPF), cerebral cortex (CTX), and plasma. Long-term consumption of the SFA diet increased ceramide and dihydroceramide in the plasma. Inhibiting de novo synthesis ameliorated this effect, while inhibition of acidic sphingomyelinase, or the sphingosine-1-phosphate receptor agonist did not. SFA feeding did not influence sphingolipid levels in either the HPF or CTX. De novo synthesis inhibition reduced ceramide in the CTX, while treatment with a sphingosine-1-phosphate receptor agonist reduced ceramides in the HPF. Analysis of the individual ceramide species revealed the effects were chain-length dependent. Both positive and negative correlations were observed between plasma and HPF/CTX ceramide species. The findings in this study show that HPF and CTX sphingolipid concentration are influenced by distinct pathways, independent of peripheral sphingolipid concentration.
authors.affiliation: Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.|School of Public Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Corey
authors.identifier: 0000-0002-6050-1259
authors.initials: C
authors.lastname: Giles
authors.affiliation: Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.|School of Public Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takechi
authors.affiliation: Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mellett
authors.affiliation: Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: School of Public Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Satvinder
authors.initials: S
authors.lastname: Dhaliwal
authors.affiliation: Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.|School of Public Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Mamo
mesh_terms: D000818:Animals; D002518:Ceramides / Q000097:blood / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D018752:Diet, Fat-Restricted; D005227:Fatty Acids / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D013107:Sphingolipids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; C001996:thermozymocidin
keywords: brain; ceramide; lipidomics; mass spectrometry; neurodegeneration