Acyl‐CoA Synthetase 6 Mediates Brain Docosahexaenoic Acid (DHA) Enrichment and Neuroprotection

Abstract

The omega‐3 fatty acid, docosahexaenoic acid (DHA), is enriched in the central nervous system and thought to protect against neurological dysfunction. Yet, studying the role of brain DHA metabolism in the development of neurological dysfunction has remained limited because the biochemical mechanisms regulating DHA enrichment in the brain remain unclear. To define a critical regulatory node in brain DHA biochemistry we targeted long chain acyl‐CoA synthetase 6 (Acsl6) because this enzyme initiates cellular fatty acid metabolism, is enriched in the brain and prefers DHA as its substrate. Genetically deleting Acsl6 in mice resulted in large and specific reductions (35–72%) in DHA‐containing phospholipids across tissues that highly express Acsl6 (i.e. the central nervous system). Acsl6−/− mice develop age‐related deleterious neurological pathology characterized by increased astrogliosis and microglia. Surprisingly, this pathology develops in the absence of alterations in pro‐ and anti‐inflammatory lipid mediators, suggesting alternative mechanisms mediating neuroinflammation in Acsl6‐induced DHA deficiency. Together our findings demonstrate a novel central nervous system DHA‐deficient model susceptible to aging‐induced neuroinflammatory pathology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.