Acyl-CoA synthetases as regulators of brain phospholipid acyl-chain diversity

Abstract

Each individual cell-type is defined by its distinct morphology, phenotype, molecular and lipidomic profile. The importance of maintaining cell-specific lipidomic profiles is exemplified by the numerous diseases, disorders, and dysfunctional outcomes that occur as a direct result of altered lipidome. Therefore, the mechanisms regulating cellular lipidome diversity play a role in maintaining essential biological functions. The brain is an organ particularly rich in phospholipids, the main constituents of cellular membranes. The phospholipid acyl-chain profile of membranes in the brain is rather diverse due in part to the high degree of cellular heterogeneity. These membranes and the acyl-chain composition of their phospholipids are highly regulated, but the mechanisms that confer this tight regulation are incompletely understood. A family of enzymes called acyl-CoA synthetases (ACSs) stands at a pinnacle step allowing influence over cellular acyl-chain selection and subsequent metabolic flux. ACSs perform the initial reaction for cellular fatty acid metabolism by ligating a Coenzyme A to a fatty acid which both traps a fatty acid within a cell and activates it for metabolism. The ACS family of enzymes is large and diverse consisting of 25-26 family members that are nonredundant, each with unique distribution across and within cell types, and differential fatty acid substrate preferences. Thus, ACSs confer a critical intracellular fatty acid selecting step in a cell-type dependent manner providing acyl-CoA moieties that serve as essential precursors for phospholipid synthesis and remodeling, and therefore serve as a key regulator of cellular membrane acyl-chain compositional diversity. Here we will discuss how the contribution of individual ACSs towards brain lipid metabolism has only just begun to be elucidated and discuss the possibilities for how ACSs may differentially regulate brain lipidomic diversity. Abbreviations LA linoleic acid ALA alpha-linolenic acid PUFA polyunsaturated fatty acids AA arachidonic acid EPA eicosapentaenoic acid DHA docosahexaenoic acid ACS acyl-CoA synthetase CoA coenzyme A

Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

“…A number of results in the literature indicate that astrocytes express ACSL6 (20,(24)(25)(26)(27)(28). To directly test the role of astrocytic ACSL6, we generated astrocyte-specific ACSL6-deficient mice using the glial fibrillary acidic protein (GFAP) promoter Cre driver (Acsl6 G-/-) (17).…”

“…Thus, ACSL6 deficiency does not cause a DHA deficit in glial cells, arguably the major cell type driving lipid mediator metabolism, thereby potentially limiting the impact of ACSL6 on lipid mediator homeostasis. Because ACSL6 expression is identified as astrocyte enriched in numerous databases (20,(24)(25)(26)(27)(28), we were surprised that the loss of ACSL6 in astrocytes had minimal impact on brain membrane lipid composition. However, these databases use cells derived from animals early in development, failing to capture transcripts, such as Acsl6, that present in latestage mature neurons.…”

“…This enzymatic activity both traps free fatty acids within cells and also activates fatty acids for subsequent intracellular metabolism. Each acyl-CoA synthetase enzyme has unique enzymatic preferences, regulatory mechanisms, and expression profiles across cell types, properties that contribute to cell type–specific lipid metabolism and composition ( 20 ). Here, we investigated how the loss of ACSL6 and the consequent DHA deficiency and AA enrichment within the brain affects aging.…”

Peripheral Expression Levels of Selected Oxidative Stress-Related Genes in Alzheimer’s Disease

“…Considering the fact that the brain is the fattiest organ after adipose tissue, ACSL4 is regarded as an important enzyme for neurodegenerative diseases due to its role in lipid metabolism although it has not been fully investigated in AD (25). An in vitro study of embryonic stem cells showed that the nerve growth factor, retinoic acid induced neuronal differentiation, and neurite growth were weakened by a knockout of the ACSL4 gene (26).…”

Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer’s disease in humans

“…Rat monoclonal antibodies were raised against lipid peroxidation-modified ApoE by incubating ApoE monomers with Cu-oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (PAPC), a phospholipid that it is particularly enriched in hippocampus. 52 Two clones (15E8 [PxPAPC-ApoEa], and 2B7 [PxPAPC-ApoEb])…”