Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function

Richard Harkewicz, Hongjun Du, Zongzhong Tong, Hisham Alkuraya, Matthew Bedell, Woong Sun, Xiaolei Wang, Yuan Hao Hsu, Julian Esteve-Rudd, Guy Hughes, Zhiguang Su, Ming Zhang, Vanda S. Lopes, Robert S. Molday, David S. Williams, Edward A. Dennis, Kang Zhang

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Abstract

Very long chain polyunsaturated fatty acid (VLC-PUFA)-containing glycerophospholipids are highly enriched in the retina; however, details regarding the specific synthesis and function of these highly unusual retinal glycerophospholipids are lacking. Elongation of very long chain fatty acids-4 (ELOVL4) has been identified as a fatty acid elongase protein involved in the synthesis of VLC-PUFAs. Mutations in ELOVL4 have also been implicated in an autosomal dominant form of Stargardt disease (STGD3), a type of juvenile macular degeneration. We have generated photoreceptor-specific conditional knock-out mice and used high performance liquid chromatography-mass spectrometry (HPLC-MS) to examine and analyze the fatty acid composition of retinal membrane glycerophosphatidylcholine and glycerophosphatidylethanolamine species. We also used immunofluorescent staining and histology coupled with electrophysiological data to assess retinal morphology and visual response. The conditional knock-out mice showed a significant decrease in retinal glycerophospholipids containing VLC-PUFAs, specifically contained in the sn-1 position of glycerophosphatidylcholine, implicating the role of Elovl4 in their synthesis. Conditional knock-out mice were also found to have abnormal accumulation of lipid droplets and lipofuscin-like granules while demonstrating photoreceptor-specific abnormalities in visual response, indicating the critical role of Elovl4 for proper rod or cone photoreceptor function. Altogether, this study demonstrates the essential role of ELOVL4 in VLC-PUFA synthesis and retinal function.

Original languageEnglish
Pages (from-to)11469-11480
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number14
DOIs
Publication statusPublished - 2012 Mar 30
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Harkewicz, R., Du, H., Tong, Z., Alkuraya, H., Bedell, M., Sun, W., Wang, X., Hsu, Y. H., Esteve-Rudd, J., Hughes, G., Su, Z., Zhang, M., Lopes, V. S., Molday, R. S., Williams, D. S., Dennis, E. A., & Zhang, K. (2012). Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. Journal of Biological Chemistry, 287(14), 11469-11480. https://doi.org/10.1074/jbc.M111.256073