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Papers In Press, published online ahead of print May 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800170-JLR200

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Journal of Lipid Research, Vol. 50, 807-819, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

High levels of retinal membrane docosahexaenoic acid increase susceptibility to stress-induced degeneration

Masaki Tanito^1,*,, Richard S. Brush^*,, Michael H. Elliott^*,, Lea D. Wicker^*,, Kimberly R. Henry^*, and Robert E. Anderson^,

^* Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Dean A. McGee Eye Institute, Oklahoma City, Oklahoma
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of nine tables.

This study was supported by grants from the National Eye Institute (EY04149, EY00871, and EY12190), National Center for Research Resources (RR17703), Research to Prevent Blindness, Inc., and the Foundation Fighting Blindness. Masaki Tanito is a recipient of a Research Fellowship from the Japan Society for the Promotion of Science (JSPS) for Young Scientists.

Published, JLR Papers in Press, November 20, 2008.

¹ To whom correspondence should be addressed. e-mail: tanito-oph{at}umin.ac.jp

The fat-1 gene cloned from C. elegans encodes an n-3 fatty acid desaturase that converts n-6 to n-3 PUFA. Mice carrying the fat-1 transgene and wild-type controls were fed an n-3-deficient/n-6-enriched diet [fat-1- safflower oil (SFO) and wt-SFO, respectively]. Fatty acid profiles of rod outer segments (ROS), cerebellum, plasma, and liver demonstrated significantly lower n-6/n-3 ratios and higher docosahexaenoic acid (DHA) levels in fat-1-SFO compared with wt-SFO. When mice were exposed to light stress: 1) the outer nuclear layer (ONL) thickness was reduced; 2) amplitudes of the electroretinogram (ERG) were lower; 3) the number of apoptotic photoreceptor cells was greater; and 4) modification of retinal proteins by 4-hydroxyhexenal (4-HHE), an end-product of n-3 PUFA oxidation was increased in both fat-1-SFO and wt mice fed a regular lab chow diet compared with wt-SFO. The results indicate a positive correlation between the level of DHA, the degree of n-3 PUFA lipid peroxidation, and the vulnerability of the retina to photooxidative stress. In mice not exposed to intense light, the reduction in DHA resulted in reduced efficacy in phototransduction gain steps, while no differences in the retinal morphology or retinal biochemistry. These results highlight the dual roles of DHA in cellular physiology and pathology.

Supplementary key words retinal light damage • fat-1 • n-3 fatty acid desaturase • 4-hydoroxynonenal (4-HNE) • 4-hydroxyhexenal (4-HHE)

Abbreviations: AMD, age-related macular degeneration; CBB, Coomassie Brilliant Blue R-250; DHA, docosahexaenoic acid; ERG, electroretinogram; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; 4-HHE, 4-hydroxyhexenal; 4-HNE, 4-hydroxynonenal; ONL, outer nuclear layer; PDE6, phosphodiesterase 6; ROS, rod outer segments; SFO, safflower oil

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