Disease relevance of ACSL4

• Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies [1].
• These findings suggest that the disruption of DMD and the absence of ACSL4 in the patient are responsible for neuromuscular disease and cognitive impairment [1].
• In order to gain a better understanding of ACSL4 fatty acid binding, we based a mutagenesis approach on sequence alignments related to ttLC-FACS crystallized from Thermus thermophilus HB8 [2].
• FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation [3].
• FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation [4].

High impact information on ACSL4

• Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation [4].
• All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage [4].
• To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as "sinks" for unesterified arachidonic acid [5].
• We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level [5].
• Here, we report that expression of FACL4 is significantly increased in colon adenocarcinoma compared with adjacent normal tissue at both the mRNA and protein levels by quantitative RT-PCR (paired t test, P < 0.015), immunoblot, and immunohistochemical staining [6].

Chemical compound and disease context of ACSL4

• AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonate-preferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis [7].
• Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema [8].
• BACKGROUND: The gene encoding fatty acid CoA ligase 4 (FACL4) is mutated in families with non-specific X linked mental retardation (MRX) and is responsible for cognitive impairment in the contiguous gene syndrome ATS-MR (Alport syndrome and mental retardation), mapped to Xq22 [9].
• Male subjects with the T0 genotype showed greater dermal erythema following topical application of methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium with a functional polymorphism of the FACL4 gene that modulates re-sequestration of agonist-released free AA [8].

Biological context of ACSL4

• In a direct competition assay with palmitate, all the polyunsaturated fatty acids tested were strong competitors only for ACSL4 with IC50 values of 0.5 to 5 microM [10].
• In an attempt to characterize the genes contributing to this complex phenotype, we have isolated a gene encoding a new long-chain acyl-CoA synthetase (FACL4 or LACS4) from the region deleted in these patients [3].
• 1alpha,25(OH)(2)D(3) had no significant effect on the expression of FACL1(FACL2), FACL4 and FACL6 except for its downregulation of FACL5 at 24 and 48h by around twofold [11].
• The onset of FACL4 up-regulation appears to occur during the transformation from adenoma to adenocarcinoma because FACL4 expression was not increased above normal in the three colon adenomas examined [6].
• A minimal promoter region required for the expression of ACS4 in HeLa S3 cells was determined [12].

Anatomical context of ACSL4

• Conversely, murine macrophages did not express ACSL4, and rosiglitazone did not inhibit ACSL activity in these cells, nor did it affect acute fatty acid partitioning into cellular lipids [13].
• Because it is unknown if ACSL4 is expressed in vascular cells involved in atherosclerosis, we investigated the ability of rosiglitazone to inhibit ACSL activity and fatty acid partitioning in human and murine arterial smooth muscle cells (SMCs) and macrophages [13].
• Human placenta, brain, testis, ovary, spleen, and adrenal cortex have the highest levels of expression of the long-chain fatty acid-CoA ligase 4, whereas the GI system has the lowest [14].
• The in situ hybridization results indicate that expression of FACL4 is localized predominantly in the colon epithelium but not in the stroma [6].
• ACS4 may provide acyl-CoA for both synthesis and peroxisomal oxidation, depending on whether the enzyme is associated with the mitochondrial-associated membrane or with peroxisomes [15].

Associations of ACSL4 with chemical compounds

• Compared to ACSL4, another brain isoform, ACSL3, ACSL6_v1, and ACSL6_v2 showed similarities in kinetic values for CoA, palmitate, and arachidonate, but their apparent Km values for oleate were 4- to 6-fold lower than for ACSL4 [10].
• Although each of the five mammalian long-chain acyl-CoA synthetases (ACSL) can bind saturated and unsaturated fatty acids ranging from 12 to 22 carbons, ACSL4 prefers longer chain polyunsaturated fatty acids [2].
• Inhibition of ACS4 and MTE-I activity by triacsin C and NDGA, respectively results in a reduction of StAR mRNA and protein abundance [16].
• FACL4 selectively esterifies these fatty acids with co-enzyme A, forming acyl-co-A, which can then be incorporated into membrane phospholipid [8].

Regulatory relationships of ACSL4

• In addition, FACL4 was highly expressed in both adult and newborn mouse brain especially in the granule cells of the dentate gyrus and the pyramidal cell layer of CA1 in hippocampus, and the granular cell layer and Purkinje cells of the cerebellum [17].

Other interactions of ACSL4

• Human and murine SMCs and human macrophages expressed Acsl4, and rosiglitazone inhibited Acsl activity in these cells [13].
• Thus, rosiglitazone inhibits ACSL activity and fatty acid partitioning in human and murine SMCs and in human macrophages through a PPAR-gamma-independent mechanism likely to be mediated by ACSL4 inhibition [13].
• ACSL3 and the two variants of ACSL6 were more resistant than ACSL4 to heat inactivation [10].
• While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene [18].
• The murine and human orthologs show 96.5% (FACL4) and 95.2% (AMMECR1) identity at the amino acid level, with conservation of the respective putative subcellular localization signals [19].

Analytical, diagnostic and therapeutic context of ACSL4

• In addition, we found that 4 out of 8 (50%) human hepatoma cell lines expressed high levels of FACL4 by northern blot analysis [20].

References