Alternative titles; symbols
HGNC Approved Gene Symbol: ALOX15B
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:8,039,059-8,049,134 (from NCBI)
The lipoxygenases are a structurally related family of nonheme iron dioxygenases that function in the production of fatty acid hydroperoxides. In humans, the 5S (ALOX5; 152390)-, 12S (ALOX12; 152391)-, and 15S (ALOX15; 152392)-lipoxygenases oxygenate arachidonic acid in different positions along the carbon chain and form the corresponding 5S-, 12S-, or 15S-hydroperoxides, respectively. ALOX15B converts arachidonic acid to 15S-hydroperoxide (summary by Brash et al., 1997).
Using a PCR strategy with degenerate primers based on the distinct regions of lipoxygenases, Brash et al. (1997) isolated human hair root cDNAs encoding ALOX15B, a novel lipoxygenase. The predicted 676-amino acid protein shares 38 to 44% sequence identity with other human lipoxygenases. Northern blot analysis detected expression of a 2.5- to 3-kb ALOX15B mRNA in lung, cornea, and prostate.
Gross (2019) mapped the ALOX15B gene to chromosome 17p13.1 based on an alignment of the ALOX15B sequence (GenBank AF468051) with the genomic sequence (GRCh38).
Brash et al. (1997) found that, when expressed in mammalian cells, human ALOX15B converted arachidonic acid exclusively to 15S-hydroperoxide. Linoleic acid was a relatively poor substrate for ALOX15B. The authors noted that ALOX15 has distinct catalytic activities and is strongly expressed in specific blood cell types, suggesting that ALOX15 and ALOX15B have distinct functions.
Using quantitative PCR, Wuest et al. (2012) showed that expression of ALOX15B mRNA increased during differentiation of human monocytes to macrophages, whereas expression of ALOX12 and ALOX15 remained low. Stimulation with IL4 (147780), IL13 (147683), lipopolysaccharide (LPS), or hypoxia further increased ALOX15B mRNA expression, but IL6 (147620) reduced it. Western blot analysis showed that IL4, LPS, and hypoxia also increased ALOX15B protein expression, whereas IL13 had no effect on protein levels.
Using recombinant proteins, Kutzner et al. (2017) showed that mammalian ALOX15 orthologs preferably oxygenated docosahexaenoic acid (DHA) in the presence of various polyunsaturated fatty acids. Human ALOX15 exhibited dual specificity with DHA, forming similar amounts of 14- and 17-hydroperoxides. In contrast, human ALOX12 and ALOX15B displayed singular specificity with DHA, forming 14- and 17-hydroperoxides, respectively.
By immunohistochemical analysis, Sandstedt et al. (2018) showed that ALOX15 and ALOX15B were expressed throughout failing hearts and donor hearts, with ALOX15 levels significantly higher in donor hearts. Quantitative RT-PCR showed that hypoxia significantly induced expression of ALOX15 and ALOX15B in cultured cardiac fibroblasts from failing hearts. Moreover, concentration of the ALOX15 reaction product 15-hydroxyeicosatetraenoic acid (15-HETE) increased under hypoxia, and addition of an ALOX15 inhibitor decreased it. Preconditioned medium from hypoxic human cardiac fibroblast cultures decreased beating frequency of cardiomyocytes derived from human-induced pluripotent stem cells in an ALOX15-dependent manner.
Snodgrass et al. (2018) found that expression of ALOX15 and ALOX15B increased in primary human macrophages following IL4 stimulation, and that increased ALOX15 elevated production of cellular 15(S)-HETE and 13(S)-hydroxyoctadecadienoic acid. Knockdown of ALOX15 reduced SREBP2 (SREBF2; 600481) levels in IL4-stimulated macrophages only, whereas knockdown of ALOX15B reduced levels of SREBP2 in both untreated and IL4-stimulated macrophages. Knockdown of ALOX15 or ALOX15B altered expression of cholesterol regulatory genes, but only silencing of ALOX15B translated into changes in cholesterol content in macrophages. Moreover, expression of ALOX15B in macrophages contributed to increased CCL17 production in an SREBP2-dependent manner, resulting in altered T-cell migration. Further analysis demonstrated that expression of ALOX15B in macrophages correlated with severity of human asthma.
Brash, A. R., Boeglin, W. E., Chang, M. S. Discovery of a second 15S-lipoxygenase in humans. Proc. Nat. Acad. Sci. 94: 6148-6152, 1997. [PubMed: 9177185] [Full Text: https://doi.org/10.1073/pnas.94.12.6148]
Gross, M. B. Personal Communication. Baltimore, Md. 9/23/2019.
Kutzner, L., Goloshchapova, K., Heydeck, D., Stehling, S., Kuhn, H., Schebb, N. H. Mammalian ALOX15 orthologs exhibit pronounced dual positional specificity with docosahexaenoic acid. Biochim. Biophys. Acta Molec. Cell Biol. Lipids 1862: 666-675, 2017. [PubMed: 28400162] [Full Text: https://doi.org/10.1016/j.bbalip.2017.04.001]
Sandstedt, M., Rotter Sopasakis, V., Lundqvist, A., Vukusic, K., Oldfors, A., Dellgren, G., Sandstedt, J., Hulten, L. M. Hypoxic cardiac fibroblasts from failing human hearts decrease cardiomyocyte beating frequency in an ALOX15 dependent manner. PLoS One 13: e0202693, 2018. Note: Electronic Article. [PubMed: 30138423] [Full Text: https://doi.org/10.1371/journal.pone.0202693]
Snodgrass, R. G., Zezina, E., Namgaladze, D., Gupta, S., Angioni, C., Geisslinger, G., Lutjohann, D., Brune, B. A novel function for 15-lipoxygenases in cholesterol homeostasis and CCL17 production in human macrophages. Front. Immun. 9: 1906, 2018. Note: Electronic Article. [PubMed: 30197642] [Full Text: https://doi.org/10.3389/fimmu.2018.01906]
Wuest, S. J. A., Crucet, M., Gemperle, C., Loretz, C., Hersberger, M. Expression and regulation of 12/15-lipooxygenases in human primary macrophages. Atherosclerosis 225: 121-127, 2012. [PubMed: 22980500] [Full Text: https://doi.org/10.1016/j.atherosclerosis.2012.07.022]