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Gene Review

ACSL4  -  acyl-CoA synthetase long-chain family...

Homo sapiens

Synonyms: ACS4, FACL4, LACS 4, LACS4, Long-chain acyl-CoA synthetase 4, ...
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Disease relevance of ACSL4


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


Biological context of ACSL4


Anatomical context of ACSL4


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


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


  1. Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies. Bhat, S.S., Schmidt, K.R., Ladd, S., Kim, K.C., Schwartz, C.E., Simensen, R.J., DuPont, B.R., Stevenson, R.E., Srivastava, A.K. Cytogenet. Genome Res. (2006) [Pubmed]
  2. Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding. Stinnett, L., Lewin, T.M., Coleman, R.A. Biochim. Biophys. Acta (2007) [Pubmed]
  3. FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation. Piccini, M., Vitelli, F., Bruttini, M., Pober, B.R., Jonsson, J.J., Villanova, M., Zollo, M., Borsani, G., Ballabio, A., Renieri, A. Genomics (1998) [Pubmed]
  4. FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Meloni, I., Muscettola, M., Raynaud, M., Longo, I., Bruttini, M., Moizard, M.P., Gomot, M., Chelly, J., des Portes, V., Fryns, J.P., Ropers, H.H., Magi, B., Bellan, C., Volpi, N., Yntema, H.G., Lewis, S.E., Schaffer, J.E., Renieri, A. Nat. Genet. (2002) [Pubmed]
  5. Intracellular unesterified arachidonic acid signals apoptosis. Cao, Y., Pearman, A.T., Zimmerman, G.A., McIntyre, T.M., Prescott, S.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. Cao, Y., Dave, K.B., Doan, T.P., Prescott, S.M. Cancer Res. (2001) [Pubmed]
  7. Involvement of fatty acid-CoA ligase 4 in hepatocellular carcinoma growth: roles of cyclic AMP and p38 mitogen-activated protein kinase. Liang, Y.C., Wu, C.H., Chu, J.S., Wang, C.K., Hung, L.F., Wang, Y.J., Ho, Y.S., Chang, J.G., Lin, S.Y. World J. Gastroenterol. (2005) [Pubmed]
  8. Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema. Covault, J., Pettinati, H., Moak, D., Mueller, T., Kranzler, H.R. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  9. A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients. Longo, I., Frints, S.G., Fryns, J.P., Meloni, I., Pescucci, C., Ariani, F., Borghgraef, M., Raynaud, M., Marynen, P., Schwartz, C., Renieri, A., Froyen, G. J. Med. Genet. (2003) [Pubmed]
  10. Characterization of recombinant long-chain rat acyl-CoA synthetase isoforms 3 and 6: identification of a novel variant of isoform 6. Van Horn, C.G., Caviglia, J.M., Li, L.O., Wang, S., Granger, D.A., Coleman, R.A. Biochemistry (2005) [Pubmed]
  11. The role of long-chain fatty-acid-CoA ligase 3 in vitamin D3 and androgen control of prostate cancer LNCaP cell growth. Qiao, S., Tuohimaa, P. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  12. Exon/intron organization and transcription units of the human acyl-CoA synthetase 4 gene. Minekura, H., Kang, M.J., Inagaki, Y., Cho, Y.Y., Suzuki, H., Fujino, T., Yamamoto, T.T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  13. Rosiglitazone Inhibits Acyl-CoA Synthetase Activity and Fatty Acid Partitioning to Diacylglycerol and Triacylglycerol via a Peroxisome Proliferator-Activated Receptor-{gamma}-Independent Mechanism in Human Arterial Smooth Muscle Cells and Macrophages. Askari, B., Kanter, J.E., Sherrid, A.M., Golej, D.L., Bender, A.T., Liu, J., Hsueh, W.A., Beavo, J.A., Coleman, R.A., Bornfeldt, K.E. Diabetes (2007) [Pubmed]
  14. Cloning, expression, and chromosomal localization of human long-chain fatty acid-CoA ligase 4 (FACL4). Cao, Y., Traer, E., Zimmerman, G.A., McIntyre, T.M., Prescott, S.M. Genomics (1998) [Pubmed]
  15. Do long-chain acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? Coleman, R.A., Lewin, T.M., Van Horn, C.G., Gonzalez-Baró, M.R. J. Nutr. (2002) [Pubmed]
  16. Arachidonic acid regulation of steroid synthesis: new partners in the signaling pathway of steroidogenic hormones. Castilla, R., Maloberti, P., Castillo, F., Duarte, A., Cano, F., Maciel, F.C., Neuman, I., Mendez, C.F., Paz, C., Podestá, E.J. Endocr. Res. (2004) [Pubmed]
  17. Expression of fatty acid-CoA ligase 4 during development and in brain. Cao, Y., Murphy, K.J., McIntyre, T.M., Zimmerman, G.A., Prescott, S.M. FEBS Lett. (2000) [Pubmed]
  18. Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome (AMME). Vitelli, F., Piccini, M., Caroli, F., Franco, B., Malandrini, A., Pober, B., Jonsson, J., Sorrentino, V., Renieri, A. Genomics (1999) [Pubmed]
  19. Identification and characterization of mouse orthologs of the AMMECR1 and FACL4 genes deleted in AMME syndrome: orthology of Xq22.3 and MmuXF1-F3. Vitelli, F., Meloni, I., Fineschi, S., Favara, F., Tiziana Storlazzi, C., Rocchi, M., Renieri, A. Cytogenet. Cell Genet. (2000) [Pubmed]
  20. Fatty acid-CoA ligase 4 is overexpressed in human hepatocellular carcinoma. Sung, Y.K., Hwang, S.Y., Park, M.K., Bae, H.I., Kim, W.H., Kim, J.C., Kim, M. Cancer Sci. (2003) [Pubmed]
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