Abstract
Elongation of Very Long chain fatty acids-4 (ELOVL4) is a fatty acid condensing enzyme that mediates biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA; ≥ C28) in a limited number of tissues. Depletion of VLC-PUFA in retinal photoreceptors leads to retinal dysfunction and likely contributes to autosomal dominant Stargardt-like macular dystrophy (STGD3) pathology. In addition, depletion of VLC-PUFA in rodent testicular tissues leads to sterility. These results suggest that VLC-PUFA synthesized in situ play a unique role that cannot be compensated for by other fatty acid species. Though liver is the major fatty acid biosynthetic organs, it does not express the ELOVL4 protein; hence, no VLC-PUFA are detected in the blood and plasma. Thus, delivery of these VLC-PUFA to target tissues to compensate for their reduction caused by disease presents a challenge. We hypothesized that expression of ELOVL4 in the liver will result in the biosynthesis of VLC-PUFA that could be transported via the bloodstream to target tissues such as retina, brain and testis. Hence, we evaluated the ability of rat hepatoma (4HIIE) and human hepatocyte (HepG2) cells to synthesize VLC-PUFA by expressing ELOVL4 in these cells. We showed that, in the presence of ELOVL4, both 4HIIE and HepG2 cells are capable of VLC-PUFA biosynthesis. We propose that transgenic expression of ELOVL4 in the liver will result in the biosynthesis of VLC-PUFA that can be transported to target.
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References
Mandal MN, Ambasudhan R, Wong PW, Gage PJ, Sieving PA, Ayyagari R (2004) Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression. Genomics 83(4):626–635
Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27(1):89–93
Agbaga MP, Brush RS, Mandal MN, Henry K, Elliott MH, Anderson RE (2008) Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci USA 105(35):12843–12848
McMahon A, Jackson SN, Woods AS, Kedzierski W (2007) A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32-C36 acyl phosphatidylcholines. FEBS Lett 581(28):5459–5463
Cameron DJ, Tong Z, Yang Z, Kaminoh J, Kamiyah S, Chen H, Zeng J, Chen Y, Luo L, Zhang K (2007) Essential role of Elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival. Int J Biol Sci 3(2):111–119
Li W, Sandhoff R, Kono M, Zerfas P, Hoffmann V, Ding BC, Proia RL, Deng CX (2007) Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci 3(2):120–128
McMahon A, Butovich IA, Kedzierski W (2011) Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. J Lipid Res 52(6):1128–1138
McMahon A, Butovich IA, Mata NL, Klein M, Ritter R 3rd, Richardson J, Birch DG, Edwards AO, Kedzierski W (2007) Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4. Mol Vis 13:258–272
Vasireddy V, Uchida Y, Salem N Jr, Kim SY, Mandal MN, Reddy GB, Bodepudi R, Alderson NL, Brown JC, Hama H, Dlugosz A, Elias PM, Holleran WM, Ayyagari R (2007) Loss of functional ELOVL4 depletes very long-chain fatty acids (> or = C28) and the unique omega-O-acylceramides in skin leading to neonatal death. Hum Mol Genet 16(5):471–482
Zadravec D, Tvrdik P, Guillou H, Haslam R, Kobayashi T, Napier JA, Capecchi MR, Jacobsson A (2011) ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice. J Lipid Res 52(2):245–255
Harkewicz R, Du H, Tong Z, Alkuraya H, Bedell M, Sun W, Wang X, Hsu YH, Esteve-Rudd J, Hughes G, Su Z, Zhang M, Lopes VS, Molday RS, Williams DS, Dennis EA, Zhang K (2012) Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem 287(14):11469–11480
Zanetti SR, Maldonado EN, Aveldano MI (2007) Doxorubicin affects testicular lipids with long-chain (C18-C22) and very long-chain (C24-C32) polyunsaturated fatty acids. Cancer Res 67(14):6973–6980
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917
Yu M, Benham AF, Logan S, Brush RS, Mandal MN, Anderson RE, Agbaga MP (2011) ELOVL4 protein preferentially elongates 20:5n3 to very long chain polyunsaturated fatty acids over 20:4n6 and 22:6n3. J Lipid Res 53(3):494–504
Support
NIH/NEI Grants EY04149, EY00871, and EY021725; National Center for Research Resources Grant RR17703; Research to Prevent Blindness, Inc.; the Foundation Fighting Blindness to REA; Hope for Vision and Knight Templar Eye Foundation Inc. grants to MPA.
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Agbaga, MP., Logan, S., Brush, R., Anderson, R. (2014). Biosynthesis of Very Long-Chain Polyunsaturated Fatty Acids in Hepatocytes Expressing ELOVL4. In: Ash, J., Grimm, C., Hollyfield, J., Anderson, R., LaVail, M., Bowes Rickman, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 801. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3209-8_79
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DOI: https://doi.org/10.1007/978-1-4614-3209-8_79
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