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. 2003 Jan;163(1):159–169. doi: 10.1093/genetics/163.1.159

Suppression of the ELO-2 FA elongation activity results in alterations of the fatty acid composition and multiple physiological defects, including abnormal ultradian rhythms, in Caenorhabditis elegans.

Marina Kniazeva 1, Matt Sieber 1, Scott McCauley 1, Kang Zhang 1, Jennifer L Watts 1, Min Han 1
PMCID: PMC1462428  PMID: 12586704

Abstract

While the general steps of fatty acid (FA) biosynthesis are well understood, the individual enzymes involved in the elongation of long chain saturated and polyunsaturated FA (PUFA) are largely unknown. Recent research indicates that these enzymes might be of considerable physiological importance for human health. We use Caenorhabditis elegans to study FA elongation activities and associated abnormal phenotypes. In this article we report that the predicted C. elegans F11E6.5/ELO-2 is a functional enzyme with the FA elongation activity. It is responsible for the elongation of palmitic acid and is involved in PUFA biosynthesis. RNAi-mediated suppression of ELO-2 causes an accumulation of palmitate and an associated decrease in the PUFA fraction in triacylglycerides and phospholipid classes. This imbalance in the FA composition results in multiple phenotypic defects such as slow growth, small body size, reproductive defects, and changes in rhythmic behavior. ELO-2 cooperates with the previously reported ELO-1 in 20-carbon PUFA production, and at least one of the enzymes must function to provide normal growth and development in C. elegans. The presented data indicate that suppression of a single enzyme of the FA elongation machinery is enough to affect various organs and systems in worms. This effect resembles syndromic disorders in humans.

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Selected References

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  1. Beaudoin F., Michaelson L. V., Hey S. J., Lewis M. J., Shewry P. R., Sayanova O., Napier J. A. Heterologous reconstitution in yeast of the polyunsaturated fatty acid biosynthetic pathway. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6421–6426. doi: 10.1073/pnas.110140197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bhathena S. J. Relationship between fatty acids and the endocrine system. Biofactors. 2000;13(1-4):35–39. doi: 10.1002/biof.5520130107. [DOI] [PubMed] [Google Scholar]
  3. Chawla A., Repa J. J., Evans R. M., Mangelsdorf D. J. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001 Nov 30;294(5548):1866–1870. doi: 10.1126/science.294.5548.1866. [DOI] [PubMed] [Google Scholar]
  4. Chen C. A., Manning D. R. Regulation of G proteins by covalent modification. Oncogene. 2001 Mar 26;20(13):1643–1652. doi: 10.1038/sj.onc.1204185. [DOI] [PubMed] [Google Scholar]
  5. Chinetti G., Fruchart J. C., Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall. Z Kardiol. 2001;90 (Suppl 3):125–132. doi: 10.1007/s003920170034. [DOI] [PubMed] [Google Scholar]
  6. Dal Santo P., Logan M. A., Chisholm A. D., Jorgensen E. M. The inositol trisphosphate receptor regulates a 50-second behavioral rhythm in C. elegans. Cell. 1999 Sep 17;98(6):757–767. doi: 10.1016/s0092-8674(00)81510-x. [DOI] [PubMed] [Google Scholar]
  7. Dobrosotskaya I. Y., Seegmiller A. C., Brown M. S., Goldstein J. L., Rawson R. B. Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science. 2002 May 3;296(5569):879–883. doi: 10.1126/science.1071124. [DOI] [PubMed] [Google Scholar]
  8. Duchén K., Björkstén B. Polyunsaturated n-3 fatty acids and the development of atopic disease. Lipids. 2001 Sep;36(9):1033–1042. doi: 10.1007/s11745-001-0814-5. [DOI] [PubMed] [Google Scholar]
  9. Freeman M. P. Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry. 2000 Sep;12(3):159–165. doi: 10.1023/a:1009069002816. [DOI] [PubMed] [Google Scholar]
  10. Funk C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001 Nov 30;294(5548):1871–1875. doi: 10.1126/science.294.5548.1871. [DOI] [PubMed] [Google Scholar]
  11. Hajra A. K. On extraction of acyl and alkyl dihydroxyacetone phosphate from incubation mixtures. Lipids. 1974 Aug;9(8):502–505. doi: 10.1007/BF02532495. [DOI] [PubMed] [Google Scholar]
  12. Hannun Y. A., Luberto C., Argraves K. M. Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry. 2001 Apr 24;40(16):4893–4903. doi: 10.1021/bi002836k. [DOI] [PubMed] [Google Scholar]
  13. Hida A., Uchijima Y., Seyama Y. Sexual differences in branched chain amino acid metabolism into fatty acids and cholesterol in Harderian gland of golden hamster. J Biochem. 1998 Sep;124(3):648–653. doi: 10.1093/oxfordjournals.jbchem.a022161. [DOI] [PubMed] [Google Scholar]
  14. Hla T., Lee M. J., Ancellin N., Paik J. H., Kluk M. J. Lysophospholipids--receptor revelations. Science. 2001 Nov 30;294(5548):1875–1878. doi: 10.1126/science.1065323. [DOI] [PubMed] [Google Scholar]
  15. Horrobin D. F. Abnormal membrane concentrations of 20 and 22-carbon essential fatty acids: a common link between risk factors and coronary and peripheral vascular disease? Prostaglandins Leukot Essent Fatty Acids. 1995 Dec;53(6):385–396. doi: 10.1016/0952-3278(95)90101-9. [DOI] [PubMed] [Google Scholar]
  16. Inagaki Katsuya, Aki Tsunehiro, Fukuda Yoshihiro, Kawamoto Seiji, Shigeta Seiko, Ono Kazuhisa, Suzuki Osamu. Identification and expression of a rat fatty acid elongase involved in the biosynthesis of C18 fatty acids. Biosci Biotechnol Biochem. 2002 Mar;66(3):613–621. doi: 10.1271/bbb.66.613. [DOI] [PubMed] [Google Scholar]
  17. Jansen G. A., Hogenhout E. M., Ferdinandusse S., Waterham H. R., Ofman R., Jakobs C., Skjeldal O. H., Wanders R. J. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Hum Mol Genet. 2000 May 1;9(8):1195–1200. doi: 10.1093/hmg/9.8.1195. [DOI] [PubMed] [Google Scholar]
  18. Jansen G. A., Ofman R., Ferdinandusse S., Ijlst L., Muijsers A. O., Skjeldal O. H., Stokke O., Jakobs C., Besley G. T., Wraith J. E. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet. 1997 Oct;17(2):190–193. doi: 10.1038/ng1097-190. [DOI] [PubMed] [Google Scholar]
  19. Jump Donald B. Dietary polyunsaturated fatty acids and regulation of gene transcription. Curr Opin Lipidol. 2002 Apr;13(2):155–164. doi: 10.1097/00041433-200204000-00007. [DOI] [PubMed] [Google Scholar]
  20. Kniazeva M. F., Chiang M. F., Cutting G. R., Zack D. J., Han M., Zhang K. Clinical and genetic studies of an autosomal dominant cone-rod dystrophy with features of Stargardt disease. Ophthalmic Genet. 1999 Jun;20(2):71–81. doi: 10.1076/opge.20.2.71.2287. [DOI] [PubMed] [Google Scholar]
  21. Kniazeva M., Chiang M. F., Morgan B., Anduze A. L., Zack D. J., Han M., Zhang K. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am J Hum Genet. 1999 May;64(5):1394–1399. doi: 10.1086/302377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kniazeva M., Traboulsi E. I., Yu Z., Stefko S. T., Gorin M. B., Shugart Y. Y., O'Connell J. R., Blaschak C. J., Cutting G., Han M. A new locus for dominant drusen and macular degeneration maps to chromosome 6q14. Am J Ophthalmol. 2000 Aug;130(2):197–202. doi: 10.1016/s0002-9394(00)00585-7. [DOI] [PubMed] [Google Scholar]
  23. Komoroski R. A., Pearce J. M., Griffin W. S., Mrak R. E., Omori M., Karson C. N. Phospholipid abnormalities in postmortem schizophrenic brains detected by 31P nuclear magnetic resonance spectroscopy: a preliminary study. Psychiatry Res. 2001 May 30;106(3):171–180. doi: 10.1016/s0925-4927(01)00081-6. [DOI] [PubMed] [Google Scholar]
  24. Leonard A. E., Bobik E. G., Dorado J., Kroeger P. E., Chuang L. T., Thurmond J. M., Parker-Barnes J. M., Das T., Huang Y. S., Mukerji P. Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. Biochem J. 2000 Sep 15;350(Pt 3):765–770. [PMC free article] [PubMed] [Google Scholar]
  25. Liu D. W., Thomas J. H. Regulation of a periodic motor program in C. elegans. J Neurosci. 1994 Apr;14(4):1953–1962. doi: 10.1523/JNEUROSCI.14-04-01953.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Logue J. A., de Vries A. L., Fodor E., Cossins A. R. Lipid compositional correlates of temperature-adaptive interspecific differences in membrane physical structure. J Exp Biol. 2000 Jul;203(Pt 14):2105–2115. doi: 10.1242/jeb.203.14.2105. [DOI] [PubMed] [Google Scholar]
  27. Madani S., Hichami A., Legrand A., Belleville J., Khan N. A. Implication of acyl chain of diacylglycerols in activation of different isoforms of protein kinase C. FASEB J. 2001 Dec;15(14):2595–2601. doi: 10.1096/fj.01-0753int. [DOI] [PubMed] [Google Scholar]
  28. Miquel M., Browse J. Arabidopsis mutants deficient in polyunsaturated fatty acid synthesis. Biochemical and genetic characterization of a plant oleoyl-phosphatidylcholine desaturase. J Biol Chem. 1992 Jan 25;267(3):1502–1509. [PubMed] [Google Scholar]
  29. Moon Y. A., Shah N. A., Mohapatra S., Warrington J. A., Horton J. D. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem. 2001 Sep 20;276(48):45358–45366. doi: 10.1074/jbc.M108413200. [DOI] [PubMed] [Google Scholar]
  30. Napier J. A., Michaelson L. V. Genomic and functional characterization of polyunsaturated fatty acid biosynthesis in Caenorhabditis elegans. Lipids. 2001 Aug;36(8):761–766. doi: 10.1007/s11745-001-0782-9. [DOI] [PubMed] [Google Scholar]
  31. Peyou-Ndi M. M., Watts J. L., Browse J. Identification and characterization of an animal delta(12) fatty acid desaturase gene by heterologous expression in Saccharomyces cerevisiae. Arch Biochem Biophys. 2000 Apr 15;376(2):399–408. doi: 10.1006/abbi.2000.1733. [DOI] [PubMed] [Google Scholar]
  32. Seegmiller Adam C., Dobrosotskaya Irina, Goldstein Joseph L., Ho Y. K., Brown Michael S., Rawson Robert B. The SREBP pathway in Drosophila: regulation by palmitate, not sterols. Dev Cell. 2002 Feb;2(2):229–238. doi: 10.1016/s1534-5807(01)00119-8. [DOI] [PubMed] [Google Scholar]
  33. Watts Jennifer L., Browse John. Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2002 Apr 23;99(9):5854–5859. doi: 10.1073/pnas.092064799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zhang K., Kniazeva M., Han M., Li W., Yu Z., Yang Z., Li Y., Metzker M. L., Allikmets R., Zack D. J. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet. 2001 Jan;27(1):89–93. doi: 10.1038/83817. [DOI] [PubMed] [Google Scholar]

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