title: Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Harkewicz
authors.forename: Hongjun
authors.initials: H
authors.lastname: Du
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.forename: Matthew
authors.initials: M
authors.lastname: Bedell
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.forename: Yuan-Hao
authors.initials: YH
authors.lastname: Hsu
authors.forename: Julian
authors.initials: J
authors.lastname: Esteve-Rudd
authors.forename: Guy
authors.initials: G
authors.lastname: Hughes
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Su
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Vanda S
authors.initials: VS
authors.lastname: Lopes
authors.forename: Robert S
authors.initials: RS
authors.lastname: Molday
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D055724:Electrophysiological Phenomena; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis* / Q000737:chemistry*; D055786:Gene Knockout Techniques; D020404:Glycerophospholipids / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010767:Phosphorylcholine / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005231:Fatty Acids, Unsaturated; D020404:Glycerophospholipids; D008565:Membrane Proteins; D010767:Phosphorylcholine