High levels of retinal membrane docosahexaenoic acid increase susceptibility to stress-induced degeneration.
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.
Tanito
Masaki
M
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Brush
Richard S
RS
Elliott
Michael H
MH
Wicker
Lea D
LD
Henry
Kimberly R
KR
Anderson
Robert E
RE
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D004041:Dietary Fats; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004596:Electroretinography; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008027:Light; D055537:Light Signal Transduction / Q000502:physiology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012160:Retina / Q000737:chemistry / Q000166:cytology; D012162:Retinal Degeneration / Q000378:metabolism*; D012374:Rod Cell Outer Segment / Q000737:chemistry / Q000648:ultrastructure; D012450:Safflower Oil / Q000008:administration & dosage / Q000737:chemistry; D013312:Stress, Physiological; D019076:Transgenes
D000447:Aldehydes; D029742:Caenorhabditis elegans Proteins; D015853:Cysteine Proteinase Inhibitors; D004041:Dietary Fats; C466741:fat-1 protein, C elegans; D004281:Docosahexaenoic Acids; D012450:Safflower Oil; D044943:Fatty Acid Desaturases; C027576:4-hydroxy-2-nonenal