The ACSL4 gene is located on the X-chromosome, with its specific location being Xq22.3-q23. The gene contains 17 exons.[3] ASCL4 encodes a 74.4 kDa protein, FACL4, which is composed of 670 amino acids; 17 peptides have been observed through mass spectrometry data.[4][5]
Function
Fatty acid-CoA ligase 4 (FACL4), the protein encoded by the ACSL4 gene, is an acyl-CoA synthetase, which is an essential class of lipid metabolism enzymes, and ACSL4 is distinguished by its preference for arachidonic acid.[6] The enzyme controls the level of this fatty acid in cells; because AA is known to induce apoptosis, the enzyme modulates apoptosis.[7] Overexpression of ACSL4 results in a higher rate of arachidonoyl-CoA synthesis, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Additionally, ACSL4 regulates PGE₂ release from human smooth muscle cells. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall.[8]
Clinical significance
The most common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered FA composition of plasma phosphatidylcholines in patients with Metabolic Syndrome.[9]
It has been implicated in many mechanisms of carcinogenesis and neuronal development.[6]
Cancer
In breast cancer, ACSL4 can serve as both a biomarker for and mediator of an aggressive breast cancer phenotype. ACSL4 also is positively correlated with a unique subtype of triple negative breast cancer (TNBC), which is characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC).[10]
The encoded protein FACL4 also plays a role in the growth of hepatic cancer cells. Inhibiting FACL4 leads to inhibition of human liver tumor cells, as marked by an increased level of apoptosis.[11] It has also been suggested that modulation of FACL4 expression/activity is an approach for treatment of hepatic cell carcinoma (HCC).[7]
The FACL4 pathway is also important in colon carcinogenesis; the development of selective inhibitors for FACL4 may be a worthy effort in the prevention and treatment of colon cancer. FACL4 up-regulation appears to occur during the transformation from the cancer from adenoma to adenocarcinoma. Additionally, some colon tumor promoters significantly induced FACL4 expression.[12]
Neuronal development
FACL4 was the gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.[13] Since the ASCL4 gene is highly expressed in brain, where it encodes a brain specific isoform, a FACL4 mutation may be an efficient diagnostic tool in mentally retarded males.[14] FACL4was discovered to bedeleted in a family with Alport syndrome and elliptocytosis.[15]
↑Piccini M, Vitelli F, Bruttini M, Pober BR, Jonsson JJ, Villanova M, Zollo M, Borsani G, Ballabio A, Renieri A (Apr 1998). "FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation". Genomics. 47 (3): 350–8. doi:10.1006/geno.1997.5104. PMID9480748.
↑Verot L, Alloisio N, Morle L, Bozon M, Touraine R, Plauchu H, Edery P (Sep 2003). "Localization of a non-syndromic X-linked mental retardation gene (MRX80) to Xq22-q24". Am J Med Genet A. 122A (1): 37–41. doi:10.1002/ajmg.a.20221. PMID12949969.
↑Zeman, M; Vecka, M; Jáchymová, M; Jirák, R; Tvrzická, E; Stanková, B; Zák, A (April 2009). "Fatty acid CoA ligase-4 gene polymorphism influences fatty acid metabolism in metabolic syndrome, but not in depression". The Tohoku journal of experimental medicine. 217 (4): 287–93. doi:10.1620/tjem.217.287. PMID19346733.
↑Hu, C; Chen, L; Jiang, Y; Li, Y; Wang, S (January 2008). "The effect of fatty acid-CoA ligase 4 on the growth of hepatic cancer cells". Cancer biology & therapy. 7 (1): 131–4. doi:10.4161/cbt.7.1.5198. PMID18059177.
↑Cao, Y; Dave, KB; Doan, TP; Prescott, SM (1 December 2001). "Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma". Cancer Research. 61 (23): 8429–34. PMID11731423.
↑Meloni, I; Muscettola, M; Raynaud, M; Longo, I; Bruttini, M; Moizard, MP; Gomot, M; Chelly, J; des Portes, V; Fryns, JP; Ropers, HH; Magi, B; Bellan, C; Volpi, N; Yntema, HG; Lewis, SE; Schaffer, JE; Renieri, A (April 2002). "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation". Nature Genetics. 30 (4): 436–40. doi:10.1038/ng857. PMID11889465.
↑Piccini, M; Vitelli, F; Bruttini, M; Pober, BR; Jonsson, JJ; Villanova, M; Zollo, M; Borsani, G; Ballabio, A; Renieri, A (1 February 1998). "FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation". Genomics. 47 (3): 350–8. doi:10.1006/geno.1997.5104. PMID9480748.
Knights KM, Jones ME (1992). "Inhibition kinetics of hepatic microsomal long chain fatty acid-CoA ligase by 2-arylpropionic acid non-steroidal anti-inflammatory drugs". Biochem. Pharmacol. 43 (7): 1465–71. doi:10.1016/0006-2952(92)90203-U. PMID1567471.
Cao Y, Traer E, Zimmerman GA, et al. (1998). "Cloning, expression, and chromosomal localization of human long-chain fatty acid-CoA ligase 4 (FACL4)". Genomics. 49 (2): 327–30. doi:10.1006/geno.1998.5268. PMID9598324.
Knights KM, Gasser R, Klemisch W (2000). "In vitro metabolism of acitretin by human liver microsomes: evidence of an acitretinoyl-coenzyme A thioester conjugate in the transesterification to etretinate". Biochem. Pharmacol. 60 (4): 507–16. doi:10.1016/S0006-2952(00)00339-7. PMID10874125.
Cao Y, Dave KB, Doan TP, Prescott SM (2002). "Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma". Cancer Res. 61 (23): 8429–34. PMID11731423.
Meloni I, Muscettola M, Raynaud M, et al. (2002). "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation". Nat. Genet. 30 (4): 436–40. doi:10.1038/ng857. PMID11889465.
Sung YK, Hwang SY, Park MK, et al. (2003). "Fatty acid-CoA ligase 4 is overexpressed in human hepatocellular carcinoma". Cancer Sci. 94 (5): 421–4. doi:10.1111/j.1349-7006.2003.tb01458.x. PMID12824887.
Mashek DG, Bornfeldt KE, Coleman RA, et al. (2005). "Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family". J. Lipid Res. 45 (10): 1958–61. doi:10.1194/jlr.E400002-JLR200. PMID15292367.
Liang YC, Wu CH, Chu JS, et al. (2005). "Involvement of fatty acid-CoA ligase 4 in hepatocellular carcinoma growth: roles of cyclic AMP and p38 mitogen-activated protein kinase". World J. Gastroenterol. 11 (17): 2557–63. PMID15849811.
Bhat SS, Schmidt KR, Ladd S, et al. (2006). "Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies". Cytogenet. Genome Res. 112 (1–2): 170–5. doi:10.1159/000087531. PMID16276108.
Sung YK, Park MK, Hong SH, et al. (2007). "Regulation of cell growth by fatty acid-CoA ligase 4 in human hepatocellular carcinoma cells". Exp. Mol. Med. 39 (4): 477–82. doi:10.1038/emm.2007.52. PMID17934335.