HGNC Approved Gene Symbol: FASN
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:82,078,338-82,098,236 (from NCBI)
Fatty acid synthase (EC 2.3.1.85) catalyzes the conversion of acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids (Wakil, 1989). In prokaryotes and plants, FASN consists of an acyl carrier protein and 7 structurally independent monofunctional enzymes. In animals, however, all of the component enzymatic activities of FASN and acyl carrier protein are organized in one large polypeptide chain.
Jayakumar et al. (1994) isolated and sequenced cDNA clones representing the 2 ends of the human FASN gene and also isolated overlapping genomic clones from human YAC libraries.
Jayakumar et al. (1995) purified fatty acid synthase to near homogeneity from a human hepatoma cell line, HepG2. The specific activity of the enzyme was found to be half that of chicken liver enzyme. They also cloned the human brain FASN cDNA. The cDNA sequence had an open reading frame of 7,512 bp that encoded a 2504-amino acid protein with relative mass of 272,516. The amino acid sequence of the human enzyme had 79% and 63% identity, respectively, with the sequences of the rat and chicken enzymes. Northern analysis revealed that human FASN mRNA is about 9.3 kb in size and that its level varies among human tissues, with brain, lung, and liver tissues showing prominent expression. Sequence variants of unknown origin and significance were found in the enzyme derived from HepG2.
Ye et al. (2000) investigated the expression of ESR1 in prostate cancer cell lines and unexpectedly found a FASN/ESR1 fusion transcript. Using semi-nested RT-PCR analysis of ESR1 and its variants, Ye et al. (2000) found that the N-terminal coding region of FASN containing domain 1 was fused to the C-terminal coding region of the ESR1 ligand binding domain. Nested RT-PCR also detected the fusion transcript in breast, cervical, and bladder cancer cell lines.
Loftus et al. (2000) identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase inhibitors (cerulenin and C75, a synthetic compound) led to inhibition of feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y (162640) in the hypothalamus and acted in a leptin (164160)-independent manner that appears to be mediated by malonyl-CoA. Loftus et al. (2000) suggested that FASN may represent an important link in feeding regulation and may be a potential therapeutic target for obesity.
Camassei et al. (2003) found that FAS activation increased with increased retinoblastoma (180200) aggressiveness and postulated that FAS inhibition could represent an alternative treatment strategy in advanced and resistant retinoblastomas.
Menendez et al. (2004) identified a molecular link between FASN and the HER2 oncogene (164870), a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacologic FASN inhibitors were found to suppress p185(HER2) oncoprotein expression and tyrosine kinase activity in breast and ovarian cancers overexpressing HER2. Similar suppression was observed when FASN gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi).
Using a focused RNAi analysis, followed by validation with pharmacologic inhibitors, Heaton et al. (2010) identified 3 cellular pathways required for dengue virus (DENV; see 614371) replication: autophagy, actin polymerization, and fatty acid biosynthesis. They identified FASN as a key enzyme in the fatty acid biosynthetic pathway and showed that FASN relocalized to sites of DENV replication. DENV nonstructural protein-3 (NS3) colocalized with FASN and interacted with FASN in a 2-hybrid assay. Purified recombinant NS3 stimulated FASN activity in vitro. Heaton et al. (2010) proposed that DENV co-opts the fatty acid biosynthesis pathway to establish replication complexes.
Knobloch et al. (2013) demonstrated that Fasn, the key enzyme of de novo lipogenesis, is highly active in adult neural stem and progenitor cells (NSPCs) and that conditional deletion of Fasn in mouse NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14 (601926), a gene implicated in lipid metabolism, that Knobloch et al. (2013) found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for Fasn to fuel lipogenesis. Knobloch et al. (2013) concluded that they identified a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.
Wei et al. (2016) demonstrated that macrophage FAS (FASN) is indispensable for diet-induced inflammation. In mice, deleting Fasn in macrophages prevented diet-induced insulin resistance, recruitment of macrophages to adipose tissue, and chronic inflammation. Wei et al. (2016) found that FAS deficiency alters membrane order and composition, impairing the retention of plasma membrane cholesterol and disrupting Rho GTPase trafficking, a process required for cell adhesion, migration, and activation. Expression of a constitutively active Rho GTPase, however, restored inflammatory signaling. Exogenous palmitate was partitioned to different pools from endogenous lipids and did not rescue inflammatory signaling. However, exogenous cholesterol, as well as other planar sterols, did rescue signaling, with cholesterol restoring FAS-induced perturbations in membrane order. Wei et al. (2016) concluded that their results showed that the production of endogenous fat in macrophages is necessary for the development of exogenous fat-induced insulin resistance through the creation of a receptive environment at the plasma membrane for the assembly of cholesterol-dependent signaling networks.
Crystal Structure
Maier et al. (2008) determined the crystal structure of fatty acid synthase at 3.2-angstrom resolution covering 5 catalytic domains, whereas the flexibly tethered acyl carrier protein and thioesterase domains remain unresolved. The structure revealed a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identified 2 additional nonenzymatic domains: a pseudoketoreductase and a peripheral pseudomethyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases showed how their segmental construction allows the variation of domain composition to achieve diverse product synthesis.
By fluorescence in situ hybridization, Jayakumar et al. (1994) mapped the FASN gene to 17q25. Southern analyses suggested that a single 40-kb cosmid clone encompasses the entire coding region of the gene.
Associations Pending Confirmation
To detect a genetic component to uterine leiomyomata (150699) predisposition, Eggert et al. (2012) performed genomewide association studies in 2 independent cohorts of white women and conducted a metaanalysis. They identified 1 SNP (rs4247357) with significant association (p = 3.05 x 10(-8), odds ratio = 1.299) under a linkage peak and in a block of linkage disequilibrium in 17q25.3 that included the FASN gene. By tissue microarray immunohistochemistry, Eggert et al. (2012) found elevated (3-fold) FAS levels in uterine leiomyomata-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival.
In animals, including humans, the source of long chain saturated fatty acids is either de novo synthesis, which is mediated by fatty acid synthase, ingested food, or both. To understand the importance of de novo fatty acid synthesis, Chirala et al. (2003) generated Fasn knockout mice. The heterozygous mutant mice were ostensibly normal; however, levels of Fasn mRNA and activity were approximately 50% and 35% lower, respectively, than those of wildtype mice. When the heterozygous mutant mice were interbred, no null mice were produced; thus, Fasn is essential during embryonic development. Furthermore, the number of heterozygous progeny was 70% less than predicted by Mendelian inheritance, indicating partial haploid insufficiency. Even when 1 parent was wildtype and the other heterozygous, the estimated loss of heterozygous progeny was 60%. Most of the Fasn-null embryos died before implantation and the heterozygous embryos died at various stages of development. Feeding the breeders a diet rich in saturated fatty acids did not prevent the loss of homo- or heterozygotes.
Casado et al. (1999) stated that the E box within the FASN promoter is regulated by USF1 (191523), USF2 (600390), and SREBP1 (184756). They analyzed the glucose responsiveness of hepatic Fasn gene expression in Usf1 and Usf2 knockout mice and found that in both types of mutant mice, induction of the Fasn gene by refeeding a carbohydrate-rich diet was severely delayed. In contrast, expression of Srebp1 was almost normal, and insulin response was unchanged. Casado et al. (1999) concluded that the USF transactivators, and especially USF1/USF2 heterodimers, are essential to sustain the dietary induction of the FASN gene in liver.
Camassei, F. D., Cozza, R., Acquaviva, A., Jerkner, A., Rava, L., Gareri, R., Donfrancesco, A., Basman, C., Vadala, P., Hadjistilianou, T., Boldrini, R. Expression of the lipogenic enzyme fatty acid synthase (FAS) in retinoblastoma and its correlation with tumor aggressiveness. Invest. Ophthal. Vis. Sci. 44: 2399-2403, 2003. [PubMed: 12766036] [Full Text: https://doi.org/10.1167/iovs.02-0934]
Casado, M., Vallet, V. S., Kahn, A., Vaulont, S. Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274: 2009-2013, 1999. [PubMed: 9890958] [Full Text: https://doi.org/10.1074/jbc.274.4.2009]
Chirala, S. S., Chang, H., Matzuk, M., Abu-Elheiga, L., Mao, J., Mahon, K., Finegold, M., Wakil, S. J. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc. Nat. Acad. Sci. 100: 6358-6363, 2003. [PubMed: 12738878] [Full Text: https://doi.org/10.1073/pnas.0931394100]
Eggert, S. L., Huyck, K. L., Somasundaram, P., Kavalla, R., Stewart, E. A., Lu, A. T., Painter, J. N., Montgomery, G. W., Medland, S. E., Nyholt, D. R., Treloar, S. A., Zondervan, K. T. {and 9 others}: Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata. Am. J. Hum. Genet. 91: 621-628, 2012. [PubMed: 23040493] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.009]
Heaton, N. S., Perera, R., Berger, K. L., Khadka, S., LaCount, D. J., Kuhn, R. J., Randall, G. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc. Nat. Acad. Sci. 107: 17345-17350, 2010. [PubMed: 20855599] [Full Text: https://doi.org/10.1073/pnas.1010811107]
Jayakumar, A., Chirala, S. S., Chinault, A. C., Baldini, A., Abu-Elheiga, L., Wakil, S. J. Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene. Genomics 23: 420-424, 1994. [PubMed: 7835891] [Full Text: https://doi.org/10.1006/geno.1994.1518]
Jayakumar, A., Tai, M.-H., Huang, W.-Y., Al-Feel, W., Hsu, M., Abu-Elheiga, L., Chirala, S. S., Wakil, S. J. Human fatty acid synthase: properties and molecular cloning. Proc. Nat. Acad. Sci. 92: 8695-8699, 1995. [PubMed: 7567999] [Full Text: https://doi.org/10.1073/pnas.92.19.8695]
Knobloch, M., Braun, S. M. G., Zurkirchen, L., von Schoultz, C., Zamboni, N., Arauzo-Bravo, M. J, Kovacs, W. J., Karalay, O., Suter, U., Machado, R. A. C., Roccio, M., Lutolf, M. P., Semenkovich, C. F., Jessberger, S. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493: 226-230, 2013. [PubMed: 23201681] [Full Text: https://doi.org/10.1038/nature11689]
Loftus, T. M., Jaworsky, D. E., Frehywot, G. L., Townsend, C. A., Ronnett, G. V., Lane, M. D., Kuhajda, F. P. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288: 2379-2381, 2000. [PubMed: 10875926] [Full Text: https://doi.org/10.1126/science.288.5475.2379]
Maier, T., Leibundgut, M., Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321: 1315-1322, 2008. [PubMed: 18772430] [Full Text: https://doi.org/10.1126/science.1161269]
Menendez, J. A., Vellon, L., Mehmi, I., Oza, B. P., Ropero, S., Colomer, R., Lupu, R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Nat. Acad. Sci. 101: 10715-10720, 2004. [PubMed: 15235125] [Full Text: https://doi.org/10.1073/pnas.0403390101]
Wakil, S. J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 28: 4523-4530, 1989. [PubMed: 2669958] [Full Text: https://doi.org/10.1021/bi00437a001]
Wei, X., Song, H., Yin, L., Rizzo, M. G., Jr., Sidhu, R., Covey, D. F., Ory, D. S., Semenkovich, C. F. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539: 294-298, 2016. [PubMed: 27806377] [Full Text: https://doi.org/10.1038/nature20117]
Ye, Q., Chung, L. W. K., Li, S., Zhau, H. E. Identification of a novel FAS/ER-alpha fusion transcript expressed in human cancer cells. Biochim. Biophys. Acta 1493: 373-377, 2000. [PubMed: 11018265] [Full Text: https://doi.org/10.1016/s0167-4781(00)00202-5]