Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes

Abstract

The dysfunction of oligodendrocytes (OLs) is regarded as one of the major causes of inefficient remyelination in multiple sclerosis, resulting gradually in disease progression. Oligodendrocytes are derived from oligodendrocyte progenitor cells (OPCs), which populate the adult central nervous system, but their physiological capability to myelin synthesis is limited. The low intake of essential lipids for sphingomyelin synthesis in the human diet may account for increased demyelination and the reduced efficiency of the remyelination process. In our study on lipid profiling in an experimental autoimmune encephalomyelitis brain, we revealed that during acute inflammation, nervonic acid synthesis is silenced, which is the effect of shifting the lipid metabolism pathway of common substrates into proinflammatory arachidonic acid production. In the experiments on the human model of maturating oligodendrocyte precursor cells (hOPCs) in vitro, we demonstrated that fish oil mixture (FOM) affected the function of hOPCs, resulting in the improved synthesis of myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein, as well as sphingomyelin. Additionally, FOM reduces proinflammatory cytokines and chemokines, and enhances fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) synthesis by hOPCs was also demonstrated. Based on these observations, we propose that the intake of FOM rich in the nervonic acid ester may improve OL function, affecting OPC maturation and limiting inflammation.

Stearoyl-CoA Desaturase-2 in Murine Development, Metabolism, and Disease

“…To produce nervonoyl-CoA, the SCD2 product oleoyl-CoA is subsequently elongated by elongase-1 three times [ 56 ]. Thus, in mice, SCD2 predominately carries out the rate-limiting step of nervonoyl-CoA (C24:1n9) biosynthesis in oligodendrocytes [ 57 ].…”

“…In MS patients and experimental autoimmune encephalomyelitis rodents used as a model for MS, both sphingomyelin and nervonoyl-CoA are significantly decreased compared to control samples [ 57 , 58 ]. These data suggest that SCD2 is a critically important enzyme that controls the supply of nervonoyl-CoA (C24:1n9) for myelin biosynthesis and that inhibition of SCD2 may significantly contribute to MS [ 46 ].…”

Protective Effect of Nervonic Acid Against 6-Hydroxydopamine-Induced Oxidative Stress in PC-12 Cells

“…Impairment of NA provision has been found in the postmortem brains of individuals with demyelinating diseases such as X-ALD and MS and has been suggested as a cause of pathogenesis in these diseases 8 . Experiments using EAE mice, an animal model for MS, revealed that during acute inflammation, NA synthesis was inhibited with a shift to the synthesis of proinflammatory arachidonic acid 19 . In vitro assays of NA-containing fish oil added to cultured human oligodendrocyte precursor cells led to an enhanced maturation rate of the cells and increased synthesis of sphingomyelin.…”

“…In vitro assays of NA-containing fish oil added to cultured human oligodendrocyte precursor cells led to an enhanced maturation rate of the cells and increased synthesis of sphingomyelin. In addition, NA-containing oil was shown to inhibit the secretion of several proinflammatory factors while promoting growth factor synthesis, which is important for the regeneration of the CNS 19 . Therefore, it is sug-gested that dietary therapy with NA-rich oil may be beneficial for these neurodegenerative diseases 8 .…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…Lipid profiling in the brain of EAE mice revealed that during acute inflammation, nervonic acid synthesis is inhibited, with a shift of lipid metabolism pathway of common substrates into proinflammatory arachidonic acid production. Although its remyelinating potential has not been evaluated, cultured human OPCs exposed to nervonic acid increased their maturation rate and the synthesis of sphingolipids [25], suggesting that changing the composition of lipid metabolism may be an important and overlooked prerequisite for remyelination.…”