The gene contains 18 exons.[7] ACSL4 encodes a 74.4 kDa protein, FACL4, which is composed of 670 amino acids; 17 peptides have been observed through mass spectrometry data.[8][9]
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 (AA).[10] The enzyme controls the level of this fatty acid in cells; because AA is known to induce apoptosis (cell specific), the enzyme modulates apoptosis.[11] 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.[12]
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.[13]
It has been implicated in many mechanisms of carcinogenesis and neuronal development.[10]
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).[14]
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.[15] It has also been suggested that modulation of FACL4 expression/activity is an approach for treatment of hepatic cell carcinoma (HCC).[11]
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.[16]
Neuronal development
FACL4 was the gene shown to be involved in nonspecific intellectual disability and fatty-acid metabolism.[17] 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 intellectually disabled males.[18] FACL4 was discovered to be deleted in a family with Alport syndrome and elliptocytosis.[19]
^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. S2CID31041475.
^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. S2CID23901437.
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. S2CID23901437.
