Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration

Liu, Aihua; Chang, James; Lin, Yuan; Shen, Zhengqing; Bernstein, Paul S.

doi:10.1194/jlr.m007518

Cited by 134 publications

(123 citation statements)

References 59 publications

(60 reference statements)

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“…Decline in VLC-PUFA levels have also been associated with age in control human donor eyes as well as in patients with agerelated macular degeneration (47), suggesting an involvement of enzymes mediating fatty acid metabolism or insufficient dietary intake of VLC-PUFA precursors. Although ELOVL4 mutations/ variants have not been directly linked to the onset or progression of these age-related disorders, dietary or genetic interventions to elevate levels of VLC-PUFA in the retina may provide an avenue for therapy in alleviating or retarding maculopathies and retinal disorders that result from reduced VLC-PUFA levels.…”

Section: Discussionmentioning

confidence: 99%

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.Stargardt disease | condensing enzyme | photoreceptor degeneration

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Section: Discussionmentioning

confidence: 99%

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In the current study, we observed these VLC-PUFAs to be highly polyunsaturated, having mostly six double bonds, to a lesser extent five double bonds, and essentially no acyl chains with greater than six or fewer than five double bonds. Studies (22,23,26,35) subsequent to that of Aveldaño (34) investigating retinal glycerophospholipids have for the most part used gas chromatography-mass spectrometry (GC-MS) methodology for analysis. Note that GC-MS analysis of glycerophospholipids requires the acyl fatty acids to be first deacylated from their corresponding glycerophospholipid precursor molecule, thus creating uncertainty as to their exact precursor molecule of origin.…”

Section: Discussionmentioning

confidence: 99%

“…This elongase activity was studied using an in vitro gain-of-function approach by expressing the mouse ELOVL4 protein in rat cardiomyocytes and human RPE (23). Although ELOVL4 appears to be expressed only in tissues in which VLC-PUFAs are observed (24) and it has been noted that the retina is particularly enriched in VLC-PUFAs (23,25,26), no study to date has confirmed that ELOVL4 is indeed responsible for the biosynthesis of VLC-PUFAs in the retina. However, it has recently been reported that the epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice (27).…”

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confidence: 99%

Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function

Harkewicz

Tong

et al. 2012

Journal of Biological Chemistry

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Background: Phospholipids containing very long chain polyunsaturated fatty acids (VLC-PUFAs) are enriched in retina. Results: Specific ELOVL4 rod or cone photoreceptor conditional knock-outs cause decreases in retinal VLC-PUFAs. Conclusion: ELOVL4 is critical for the synthesis of phosphatidylcholine-containing sn-1 VLC-PUFAs and vision. Significance: ELOVL4 mutations are implicated in Stargardt disease, a type of juvenile macular degeneration.

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“…Another unique feature of retinal lipids is the abundance of phospholipids containing two PUFAs esterifi ed to the glycerol backbone, where a very long chain (24-36 carbons) (VLC)-PUFA) is located at the sn-1 position and DHA is esterifi ed at the sn-2 position ( 9 ). The functional importance of VLC-PUFAs in the retina is not well understood but VLC-PUFAs are reduced in retinas undergoing age-related macular degeneration (AMD) ( 10 ), and a key role for VLC-PUFAs has been suggested in both phototransduction regulation and photoreceptor survival ( 11,12 ).…”

Section: Maldi Imsmentioning

confidence: 99%

Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry

Berry

Gordon

Murphy

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org signals to the visual centers of the brain ( 1 ). The central region is made up of several layers that include the horizontal, bipolar, and amacrine cells, which collectively process visual information from the photoreceptors, transmitting these signals to the ganglion cells. The outermost retinal neurons, the photoreceptors, are responsible for phototransduction ( 2 ). There are two types of photoreceptors, which include rods that are present in the peripheral retina and cones that are present in the central (macular) region of the retina. Rods function in dim light and manage peripheral and night vision, whereas cones are responsible for central high acuity bright light vision. The outermost layer of the retina, the retinal pigment epithelium (RPE), serves many functions, including the isomerization of all-trans retin ol into 11-cis retin al in the visual cycle, phagocytosis and degradation of shed photoreceptor tips, and the phagocytic clearance of cellular debris resulting from apoptotic and necrotic processes ( 3 ).The lipids present in the retina are highly unique and play a critical role in retina function and disease. The retina is a tissue that is highly enriched in PUFAs with DHA (22:6) (22 carbons with 6 double bonds) accounting for approximately 50% of the fatty acids in the photoreceptors ( 4 ). This large amount of DHA results in a highly fl uid membrane that permits effi cient conformational changes to occur in rhodopsin and its associated G-protein during phototransduction ( 5 ). Moreover, DHA is converted into neuroprotectin D1, a potent mediator that evokes counteracting cell-protective anti-infl ammatory pro-survival repair signaling, including the induction of anti-apoptotic proteins and inhibition of pro-apoptotic proteins, activating signaling pathway(s) that modulate(s) pro-apoptotic Abstract MALDI imaging mass spectrometry (IMS) was used to characterize lipid species within sections of human eyes. Common phospholipids that are abundant in most tissues were not highly localized and observed throughout the accessory tissue, optic nerve, and retina. Triacylglycerols were highly localized in accessory tissue, whereas sulfatide and plasmalogen glycerophosphoethanolamine (PE) lipids with a monounsaturated fatty acid were found enriched in the optic nerve. Additionally, several lipids were associated solely with the inner retina, photoreceptors, or retinal pigment epithelium (RPE); a plasmalogen PE lipid containing DHA ( The retina is a light-sensitive multi-layered tissue that lines the back of the eye and is responsible for converting light into a neural signal. The innermost layer of the retina, which is closest to the lens, contains ganglion cells that are the output neurons which comprise the optic nerve and conduct

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Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration

Cited by 134 publications

References 59 publications

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function

Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry

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