Alternative titles; symbols
HGNC Approved Gene Symbol: SLC27A5
Cytogenetic location: 19q13.43 Genomic coordinates (GRCh38): 19:58,498,333-58,511,992 (from NCBI)
The SLC27A5 gene encodes a bile acyl CoA synthetase, which plays a role in the conjugation of taurine and glycine to bile acids (summary by Chong et al., 2012).
Fatty acids are incorporated into membranes and signaling molecules and have roles in energy storage and metabolism. These essential functions require activation of the fatty acid by acyl-coenzyme A (CoA) synthetases, such as SLC27A5, which form an activating thioester linkage between the fatty acid and CoA (Watkins et al., 2007).
Using an expression cloning strategy, Schaffer and Lodish (1994) identified a membrane protein, which they termed fatty acid transport protein, or FATP (SLC27A1; 600691), from murine adipocytes. FATP facilitates the uptake of long chain fatty acids. Hirsch et al. (1998) identified a large family of FATPs characterized by the presence of an FATP signature sequence. They identified 5 distinct FATPs in mouse and 6 different FATPs in human, which they designated FATP1 (SLC27A1), -2 (SLC27A2; 603247), -3 (SLC27A3; 604193), -4 (SLC27A4; 604194), -5 (SLC27A5), and -6 (SLC27A6; 604196). Human and mouse FATPs have unique expression patterns and are found in major organs of fatty acid metabolism, such as adipose tissue, liver, heart, and kidney.
In X-linked adrenoleukodystrophy (ALD; 300100), impaired peroxisomal beta-oxidation results in defective degradation and accumulation of very long chain fatty acids (VLCFA) in tissues and blood. Very long chain fatty acid synthetase (VLACS, or SLC27A2), an enzyme whose function is presumed missing in ALD, is highly expressed in liver and kidney, but is expressed at much lower levels in brain. However, brain contains high amounts of VLCFA and is the organ most affected in ALD. In an attempt to isolate a VLACS isoform with a different tissue distribution, Berger et al. (1998) used degenerate PCR to clone a mouse cDNA and a partial human cDNA encoding a VLACS-related protein, termed VLACSR. VLACSR is 43% identical to mouse VLACS and 37% identical to mouse FATP. Northern blot analysis of mouse tissues revealed that a 2.6-kb VLACSR mRNA was highly abundant in liver. Smaller VLACSR transcripts were present at low levels in brain, lung, testis, spleen, and skeletal muscle.
By searching an EST database using rat Vlcs as query, followed by screening a liver cDNA library, Steinberg et al. (1999) cloned VLCSH2. The deduced 690-amino acid protein contains 2 motifs shared with other VLCS and FATP family members. It also has an N-terminal endoplasmic reticulum (ER) targeting signal peptide, with cleavage likely between residues 109 and 110. Northern blot analysis of several human tissues detected a 2.3-kb VLCSH2 transcript expressed only in liver, and RT-PCR detected expression in a hepatoma cell line. Steinberg et al. (1999) noted that several VLCSH2 ESTs were derived from testis. Immunofluorescent localization of hepatoma or transfected COS-1 cells showed VLCSH2 associated with the ER and not with peroxisomes.
Using Northern and Western blot analyses, Doege et al. (2006) showed that FATP5 was expressed in human and mouse liver. Immunofluorescence analysis revealed that Fatp5 protein localized largely to plasma membrane of mouse hepatocytes. Immunoelectron microscopy of mouse liver showed that Fatp5 was distributed in the space of Disse, between hepatocytes and sinusoids.
By database analysis, Watkins et al. (2007) identified SLC27A5, which they called ACSVL6. The deduced 690-amino acid protein contains all 5 motifs characteristic of acyl-CoA synthetases. Phylogenetic analysis revealed that ACSVL6 belongs to a family of very long chain acyl-CoA synthetases.
Watkins et al. (2007) determined that the SLC27A5 gene contains 10 exons.
By somatic cell hybrid analysis and genomic sequence analysis, Steinberg et al. (1999) mapped the SLC27A5 gene to chromosome 19 between marker D19S418 and 19qter. Watkins et al. (2007) mapped the SLC27A5 gene to the minus strand of chromosome 19q13.43 by genomic sequence analysis.
By overexpression in COS-1 cells, Steinberg et al. (1999) found that VLCSH2 is an acyl-CoA synthetase capable of activating 24- and 26-carbon VLCFAs. Lower activity was observed with 16-carbon and branched chain fatty acid substrates.
Steinberg et al. (2000) determined that transient expression of VLCSH2, which is 26% identical and 48% similar to a bacterial bile acid:CoA ligase, activates cholate to its CoA derivative, choloyl-CoA. Other long and very long chain acyl-CoA synthetases failed to activate cholate. Steinberg et al. (2000) detected endogenous choloyl-CoA synthetase activity in a liver cell line.
Using FACS analysis, Doege et al. (2006) showed that Fatp5 knockout in mouse hepatocytes resulted in reduced FA uptake, whereas Fatp5 overexpression increased TA uptake in cultured HeLa cells.
Associations Pending Confirmation
For discussion of a possible association between a bile acid conjugation defect (see BACD1, 619232) and variation in the SLC27A5 gene, see 603314.0001.
Doege et al. (2006) found that Fatp5 -/- mice were born at mendelian ratios and were viable, fertile, and indistinguishable from wildtype when fed standard chow diet. However, Fatp5 knockout resulted in lower hepatic triglyceride and free fatty acid content, despite increased expression of fatty acid synthetase, and caused redistribution of lipids from liver to other LCFA-metabolizing tissues. Analysis of the hepatic lipom of Fatp5-knockout liver showed quantitative and qualitative alterations in line with decreased uptake of dietary LCFAs and increased de novo synthesis. These results indicated that efficient hepatocellular uptake of LCFAs, and thus liver lipid homeostasis in general, is largely a protein-mediated process requiring FATP5.
Doege et al. (2008) found that knockdown of Fatp5 resulted in robust reduction in LCFA uptake in mice. Loss of hepatic Fatp5 caused a redirection of lipids away from liver to tissues relying on other Fatp paralogs, such as Fatp6, Fatp1, and Fatp4, which protected mice from development of diet-induced hepatic steatosis and reversed obesity-induced nonalcoholic fatty liver disease (NAFLD). The effects of Fatp5 knockdown were comparable with those of genetically engineered knockout in mice. Furthermore, knockdown of Fatp5 reversed obesity-associated hepatic steatosis in already established NAFLD in mice, resulting in significantly improved whole-body energy homeostasis.
This variant is classified as a variant of unknown significance because its contribution to a bile acid conjugation defect (see BACD1, 619232) has not been confirmed.
In 2 sisters, born of consanguineous Pakistani parents, Chong et al. (2012) identified a homozygous c.1012C-T transition in the SLC27A5 gene, resulting in a his338-to-tyr (H338Y) substitution at a conserved residue. The variant, which was found by candidate gene sequencing, segregated with the disorder in the family. The proband was also homozygous for a missense N591S variant in the ABCB11 gene (603201), and her sister was heterozygous for this variant. The proband (patient AK), who was born at 27 weeks' gestation, presented in early infancy with self-limited cholestasis manifest as jaundice, conjugated hyperbilirubinemia, elevated serum transaminase levels; serum GGT was normal. Liver biopsy showed inconspicuous bile ducts, bridging fibrosis, and cholestasis. Urine and plasma showed high levels of unconjugated bile acids, consistent with an amidation defect. Treatment with UDCA and fat-soluble vitamins resulted in clinical improvement. The biochemical abnormalities had resolved by 49 weeks of age, and and at age 5 years, she was growing normally without vitamin deficiencies or coagulopathy. Her sister (patient SK) had increased serum levels of unconjugated bile acids, but did not develop cholestatic liver disease.
Hamosh (2021) noted that in the gnomAD database (v2.1.1) the H338Y variant was present at a low frequency (1.2 x 10(-5)) in only heterozygous state, and the N591S variant in the ABCB11 gene was classified as benign (frequency of 0.013 with 226 homozygotes).
Berger, J., Truppe, C., Neumann, H., Forss-Petter, S. A novel relative of the very-long-chain acyl-CoA synthetase and fatty acid transporter protein genes with a distinct expression pattern. Biochem. Biophys. Res. Commun. 247: 255-260, 1998. [PubMed: 9642112] [Full Text: https://doi.org/10.1006/bbrc.1998.8770]
Chong, C. P. K., Mills, P. B., McClean, P., Gissen, P., Bruce, C., Stahlschmidt, J., Knisely, A. S., Clayton, P. T. Bile acid-CoA ligase deficiency--a new inborn error of bile acid metabolism. J. Inherit. Metab. Dis. 35: 521-532, 2012. [PubMed: 22089923] [Full Text: https://doi.org/10.1007/s10545-011-9416-3]
Doege, H., Baillie, R. A., Ortegon, A. M., Tsang, B., Wu, Q., Punreddy, S., Hirsch, D., Watson, N., Gimeno, R. E., Stahl, A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic liver homeostasis. Gastroenterology 130: 1245-1258, 2006. [PubMed: 16618416] [Full Text: https://doi.org/10.1053/j.gastro.2006.02.006]
Doege, H., Grimm, D., Falcon, A., Tsang, B., Storm, T. A., Xu, H., Ortegon, A. M., Kazantzis, M., Kay, M. A., Stahl, A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J. Biol. Chem. 283: 22186-22192, 2008. [PubMed: 18524776] [Full Text: https://doi.org/10.1074/jbc.M803510200]
Hamosh, A. Personal Communication. Baltimore, Md. 3/17/2021.
Hirsch, D., Stahl, A., Lodish, H. F. A family of fatty acid transporters conserved from mycobacterium to man. Proc. Nat. Acad. Sci. 95: 8625-8629, 1998. [PubMed: 9671728] [Full Text: https://doi.org/10.1073/pnas.95.15.8625]
Schaffer, J. E., Lodish, H. F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 79: 427-436, 1994. [PubMed: 7954810] [Full Text: https://doi.org/10.1016/0092-8674(94)90252-6]
Steinberg, S. J., Mihalik, S. J., Kim, D. G., Cuebas, D. A., Watkins, P. A. The human liver-specific homolog of very long-chain acyl-CoA synthetase is cholate:CoA ligase. J. Biol. Chem. 275: 15605-15608, 2000. [PubMed: 10749848] [Full Text: https://doi.org/10.1074/jbc.C000015200]
Steinberg, S. J., Wang, S. J., McGuinness, M. C., Watkins, P. A. Human liver-specific very-long-chain acyl-coenzyme A synthetase: cDNA cloning and characterization of a second enzymatically active protein. Molec. Genet. Metab. 68: 32-42, 1999. [PubMed: 10479480] [Full Text: https://doi.org/10.1006/mgme.1999.2883]
Watkins, P. A., Maiguel, D., Jia, Z., Pevsner, J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J. Lipid Res. 48: 2736-2750, 2007. [PubMed: 17762044] [Full Text: https://doi.org/10.1194/jlr.M700378-JLR200]