Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family

Mashek, Douglas G.; Bornfeldt, Karin E.; Coleman, Rosalind A.; Berger, Johannes; Bernlohr, David A.; Black, Paul N.; DiRusso, Concetta C.; Farber, Steven A.; Guo, Wen; Hashimoto, Naohiro; Khodiyar, Varsha; Kuypers, Frans A.; Maltais, Lois J.; Nebert, Daniel W.; Renieri, Alessandra; Schaffer, Jean E.; Stahl, Andreas; Watkins, Paul A.; Vasiliou, Vasilis; Yamamoto, Tokuo

doi:10.1194/jlr.e400002-jlr200

Cited by 144 publications

(101 citation statements)

References 18 publications

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“…Given that five isoforms have been identified in the ACSL family, as well as splice variants of several of the isoforms, we suggest that there are distinct roles for the individual isoforms and variants (26). Numerous studies have advanced our understanding of the kinetic properties, tissue distribution and, to some degree, intracellular localization of the ACSL isoforms, but they have not directly shown that each isoform has a specific role in lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells

Mashek

McKenzie

Horn

et al. 2006

Journal of Biological Chemistry

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110

105

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Long chain acyl-CoA synthetase (ACSL) catalyzes the initial step in long chain fatty acid metabolism. Of the five mammalian ACSL isoforms cloned and characterized, ACSL5 is the only isoform found to be located, in part, on mitochondria and thus was hypothesized to be involved in fatty acid oxidation. To elucidate the specific roles of ACSL5 in fatty acid metabolism, we used adenoviralmediated overexpression of ACSL5 (Ad-ACSL5) in rat hepatoma McArdle-RH7777 cells. Confocal microscopy revealed that Ad-ACSL5 colocalized to both mitochondria and endoplasmic reticulum. When compared with cells infected with Ad-GFP, Ad-ACSL5-infected cells at 24 h after infection had 2-fold higher acyl-CoA synthetase activities and 30% higher rates of fatty acid uptake when incubated with 500 Acyl-CoA synthetase catalyzes the initial step in mammalian fatty acid metabolism. In this reaction, fatty acid, CoA, and ATP are used to form acyl-CoA and AMP. Acyl-CoAs have diverse metabolic fates within the cell and can be used to acylate proteins or be metabolized through catabolic pathways such as ␤-oxidation or anabolic pathways such as de novo synthesis and reacylation of triacylglycerol (TAG), 2 phospholipids, and cholesterol esters.To date, five isoforms of long chain acyl-CoA synthetase have been cloned and shown to possess activity toward long chain fatty acids. The unique pattern of tissue expression, subcellular localization, and differences in substrate preference among the isoforms suggests that individual isoforms have distinct functions. ACSL1, ACSL4, and ACSL5 appear to be the predominant isoforms in rat liver (1-5). ACSL1 and ACSL4 are located in liver endoplasmic reticulum and mitochondrial-associated membrane (6), an endoplasmic reticulum fraction possibly involved in lipoprotein synthesis (7). In addition, ACSL4 is also present on peroxisomes and has a marked preference for C20:4 and C20:5 (2). ACSL5 is the only isoform found in both mitochondrial membranes and endoplasmic reticulum (6) and, similar to ACSL1, has its highest preference for saturated and unsaturated fatty acids of 16 -20 carbons (1). Because ACSL5 is the only ACSL isoform known to be located on mitochondria, it is logical to speculate that it has a role in the ␤-oxidation of fatty acids. In support of this hypothesis, rat liver mitochondrial protein content of ACSL5 increases following a 48-h fast but declines when rats are refed a high sucrose diet for 24 h (6). To date, the most direct studies that focus on ACSL used triacsin C, an inhibitor of ACSL1, ACSL3, and ACSL4 but not ACSL5 or ACSL6 (8, 9). In hepatocytes obtained from fed rats, triacsin C decreases [1-14 C]oleic acid incorporation into TAG by 70% (10). In contrast, triacsin C decreases the metabolism of [1-14 C]oleic acid to phospholipids by 34% and to ASM by 33%. Therefore, inhibiting ACSL1, ACSL3, and ACSL4 decreases fatty acid incorporation into TAG more than into phospholipids or into pathways of fatty acid oxidation. Because hepatocytes express little ACSL6 (4), ACSL5 could account for the t...

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Section: Discussionmentioning

confidence: 99%

Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells

Mashek

McKenzie

Horn

et al. 2006

Journal of Biological Chemistry

Self Cite

110

105

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“…Five different acyl-CoA synthetase forms have been described, termed ACSL-1, -3, -4, -5, and -6 (59)(60)(61). Of these, ACSL-4 and ACSL-6 have been shown to exhibit some selectivity for AA, and the latter also for docosahexaenoic acid in intact cells (62,63).…”

Section: Discussionmentioning

confidence: 99%

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Pérez-Chacón

Astudillo²,

Ruipérez³

et al. 2009

The Journal of Immunology

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Cellular availability of free arachidonic acid (AA) is an important step in the production of pro- and anti-inflammatory eicosanoids. Control of free AA levels in cells is carried out by the action of phospholipase A2s and lysophospholipid acyltransferases, which are responsible for the reactions of deacylation and incorporation of AA from and into the sn-2 position of phospholipids, respectively. In this work, we have examined the pathways for AA incorporation into phospholipids in human monocytes stimulated by zymosan. Our data show that stimulated cells exhibit an enhanced incorporation of AA into phospholipids that is not secondary to an increased availability of lysophospholipid acceptors due to phospholipase A2 activation but rather reflects the receptor-regulated nature of the AA reacylation pathway. In vitro activity measurements indicate that the receptor-sensitive step of the AA reacylation pathway is the acyltransferase using lysophosphatidylcholine (lysoPC) as acceptor, and inhibition of the enzyme lysoPC acyltransferase 3 by specific small interfering RNA results in inhibition of the stimulated incorporation of AA into phospholipids. Collectively, these results define lysoPC acyltransferase 3 as a novel-signal–regulated enzyme that is centrally implicated in limiting free AA levels in activated cells.

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“…Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4].…”

Section: A Family Of Acyl-coa Synthetases Activates Intracellular Lonmentioning

confidence: 99%

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

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Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and verylong-chain fatty acids to form acyl-CoAs. Gain-and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology. A family of acyl-CoA synthetases activates intracellular long-chain fatty acidsBefore a fatty acid (FA) from an exogenous or endogenous source can enter any metabolic pathway with the exception of eicosanoid metabolism, it must first be activated to form an acyl-CoA. This activation step is catalyzed by acyl-CoA synthetase (ACS) via a two-step reaction: 1) the formation of an intermediate fatty acyl-AMP with the release of pyrophosphate, and 2) the formation of a fatty acyl-CoA with the release of AMP.The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length. This review will focus on the three subfamilies of ACS enzymes that activate long-chain and/ or very-long-chain saturated and unsaturated FAs, long-chain ACSs (ACSL), very-long-chain ACSs (FATP), and bubblegum (ACSBG) isoforms [2].The ACSL, FATP and ACSBG families include multiple isoforms, each encoded by a separate gene (Tables 1, 2). Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4]. Despite these similarities, purified ACSL and FATP isoforms and their splice variants show distinct enzyme kinetics, differences in sensitivity to inhibitors ( Role of acyl-CoA synthetases in FA channelingThe existence of 13 ACSL, FATP and ACSBG isoforms that all activate long-chain FA has suggested that each has an independent role in channeling FA within cells. Unique roles for ACS isoforms were first identified in studies of Saccharomyces cerevisiae mutants that lacked the ACS isoforms Faa1 and Faa4, and were unable to use exogenously provided fatty acids [31]. Similarly, complementation studies of ACS-deficient E. coli showed that each of the 5 rat ACSL isoforms differs in its ability to channel FA into specific pathways like phospholipid synthesis and β-oxidation [32]. The ACSL and FATP isoforms also differ in their ability to complement FA uptake and a...

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Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family

Cited by 144 publications

References 18 publications

Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells

Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

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