A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology

Wang, Xiangyu; Yu, Hao; Gao, Rong; Liu, Ming; Xie, Wenli

doi:10.1186/s40001-023-01523-7

Cited by 12 publications

(4 citation statements)

References 68 publications

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“…FA elongases (ELOVL family) catalyze the initial step in adding 2-carbon units to long chain FA to produce very long-chain FA [ 26 ]. In particular, ELOVL2 and ELOVL5 work in concert with the desaturases to produce polyunsaturated FA of increasing chain lengths [ 26 ]. Elovl2 mRNA levels in w.t.…”

Section: Resultsmentioning

confidence: 99%

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model

Ye,

Li,

González-Lamuño

et al. 2024

Preprint

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The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain fatty acids (LCFAs) and their integration into essential lipid species crucial for brain function. Through its enzymatic activity, ACSBG1 converts LCFAs into acyl-CoA derivatives, supporting vital processes like membrane formation, myelination, and energy production. Its regulatory role significantly influences neuronal growth, synaptic plasticity, and overall brain development, highlighting its importance in maintaining lipid homeostasis and proper brain function.Originally discovered in the fruit fly brain, ACSBG1 attracted attention for its potential implication in X-linked adrenoleukodystrophy (XALD) pathogenesis. Studies using Drosophila melanogaster lacking the ACSBG1 homolog, bubblegum, revealed adult neurodegeneration with elevated levels of very long-chain fatty acids (VLCFA). To explore ACSBG1’s role in fatty acid (FA) metabolism and its relevance to XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse model and examined its impact on lipid metabolism during mouse brain development.Phenotypically, Acsbg1-/-mice resembled wild type (w.t.) mice. Despite its primary expression in tissues affected by XALD, brain, adrenal gland and testis, ACSBG1 depletion did not significantly reduce total ACS enzyme activity in these tissues when using LCFA or VLCFA as substrates. However, analysis unveiled intriguing developmental and compositional changes in FA levels associated with ACSBG1 deficiency.In the adult mouse brain, ACSBG1 expression peaked in the cerebellum, with lower levels observed in other brain regions. Developmentally, ACSBG1 expression in the cerebellum was initially low during the first week of life but increased dramatically thereafter.Cerebellar FA levels were assessed in both w.t. and Acsbg1-/-mouse brains throughout development, revealing notable differences. While saturated VLCFA levels were typically high in XALD tissues and in fruit flies lacking ACSBG1, cerebella from Acsbg1-/-mice displayed lower saturated VLCFA levels, especially after about 8 days of age. Additionally, monounsaturated ω9 FA levels exhibited a similar trend as saturated VLCFA, ω3 polyunsaturated FA levels werewhile elevated in Acsbg1-/-mice.Further analysis of specific FA levels provided additional insights into potential roles for ACSBG1. Notably, the decreased VLCFA levels in Acsbg1-/-mice primarily stemmed from changes in C24:0 and C26:0, while reduced ω9 FA levels were mainly observed in C18:1 and C24:1. ACSBG1 depletion had minimal effects on saturated long-chain FA or ω6 polyunsaturated FA levels but led to significant increases in specific ω3 FA, such as C20:5 and C22:5.Moreover, the impact of ACSBG1 deficiency on the developmental expression of several cerebellar FA metabolism enzymes, including those required for synthesis of ω3 polyunsaturated FA, was assessed; these FA can potentially be converted into bioactive signaling molecules like eicosanoids and docosanoids.In conclusion, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

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Section: Resultsmentioning

confidence: 99%

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model

Ye,

Li,

González-Lamuño

et al. 2024

Preprint

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“…These pathways involved the concerted action of many key enzymes. To test if the LPC and LPE phenotype in Tet1 mutant cortices can be explained by the gene changes, we performed Gene Set Enrichment Analysis (GSEA) with a list curated genes involved in LPC and LPE biosynthesis [ 66–72 ]. We observed that LPC and LPE genes are positively enriched in Tet1 HxD’s ranked gene set (Normalized Enrichment score (NES): 1.098, FDR q-value: 0.401) and conversely negatively enriched in Tet1 KO’s ranked gene set (NES: −0.650, FDR q-value: 0.929), although they did not meet the statistical FDR cut-off (Figure S4E).…”

Section: Resultsmentioning

confidence: 99%

TET1 displays catalytic and non-catalytic functions in the adult mouse cortex

Foong,

Caldwell,

Thorvaldsen

et al. 2024

Epigenetics

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“…This led to the proposal that GM3 (d18:1-h24:1) be used for metabolic screening [ 127 ]. For cells to have the very-long-chain fatty acids identified in the ceramide components of GM3, cellular very-long-chain fatty acid (VLCFA) elongases (ELOVL1-7) had to catalyze the elongation of the typical fatty acids synthesized [ 128 ]. In the early stages of metabolic syndrome, there is an increase in proinflammatory VLCFAs (22:0, 23:0, 24:0, h24:0) in serum and adipose tissue [ 129 ].…”

Section: Contribution Of Glycan and Ceramide To Gg Functionmentioning

confidence: 99%

“…The effect of this change on GG function remains unknown. Human milk [133] Primarily C24:0,24:1, shorter chains not effective [106], predominantly ≥ C20 [133] d18:1 > d20:1 in human milk [133] Outside-in signaling [106,134]; skin problems, atherosclerosis, mitochondrial disfunction [135] GM3 H 1 : adipose, muscle, liver + serum [127,129]; mature outer retina [136] Primarily C18,22,24,24:1 w9 [137] d18:1 [137,138] d20:1 predominant in pyramidal and granular layers of the dentate gyrus [139] Type 2 diabetes, metabolic disease, and innate immune response [127][128][129] GD3 Prevalent in neuronal stem cells [140] Plasma membrane cytoplasm, ER-mitochondria-associated membranes [141] Longer-chain fatty acids > C18:0 in adult human brain [142] d18:1 > d20:1 Enhances proliferation via its roles in signal transduction (for a review, see [143])…”

Section: Contribution Of Glycan and Ceramide To Gg Functionmentioning

confidence: 99%

Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids

Schengrund

2024

IJMS

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While much has been learned about sphingolipids, originally named for their sphinx-like enigmatic properties, there are still many unanswered questions about the possible effect(s) of the composition of ceramide on the synthesis and/or behavior of a glycosphingolipid (GSL). Over time, studies of their ceramide component, the sphingoid base containing the lipid moiety of GSLs, were frequently distinct from those performed to ascertain the roles of the carbohydrate moieties. Due to the number of classes of GSLs that can be derived from ceramide, this review focuses on the possible role(s) of ceramide in the synthesis/function of just one GSL class, derived from glucosylceramide (Glc-Cer), namely sialylated ganglio derivatives, initially characterized and named gangliosides (GGs) due to their presence in ganglion cells. While much is known about their synthesis and function, much is still being learned. For example, it is only within the last 15–20 years or so that the mechanism by which the fatty acyl component of ceramide affected its transport to different sites in the Golgi, where it is used for the synthesis of Glu- or galactosyl-Cer (Gal-Cer) and more complex GSLs, was defined. Still to be fully addressed are questions such as (1) whether ceramide composition affects the transport of partially glycosylated GSLs to sites where their carbohydrate chain can be elongated or affects the activity of glycosyl transferases catalyzing that elongation; (2) what controls the differences seen in the ceramide composition of GGs that have identical carbohydrate compositions but vary in that of their ceramide and vice versa; (3) how alterations in ceramide composition affect the function of membrane GGs; and (4) how this knowledge might be applied to the development of therapies for treating diseases that correlate with abnormal expression of GGs. The availability of an updatable data bank of complete structures for individual classes of GSLs found in normal tissues as well as those associated with disease would facilitate research in this area.

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A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology

Cited by 12 publications

References 68 publications

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model

TET1 displays catalytic and non-catalytic functions in the adult mouse cortex

Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids

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