Chemistry and metabolism of lipids in the vertebrate retina

Fliesler, Steven J.; Anderson, Robert E.

doi:10.1016/0163-7827(83)90004-8

Cited by 918 publications

(572 citation statements)

References 262 publications

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“…Because the VEP measures the function of the entire visual pathway from photoreceptors to primary visual cortex, the precise site within the visual system where supplemental DHA acts to enhance vision is unknown. Retinal photoreceptor and RPE cell membranes have a high concentration, and therefore a presumed high need for DHA [38]. DHA supplementation may enhance retinal function by restoring DHA levels to a sufficient concentration in retinal photoreceptor and RPE cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency

Gillingham

Weleber

Neuringer

et al. 2005

Molecular Genetics and Metabolism

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The objective of this prospective cohort study was to determine if dietary therapy including docosahexaenoic acid (DHA; C22:6ω-3) supplementation prevents the progression of the severe chorioretinopathy that develops in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Physical, biochemical, and ophthalmological evaluations, including electroretinogram (ERG) and visual acuity by evoked potential (VEP), were performed at baseline and annually following the initiation of 65-130 mg/day DHA supplementation and continued treatment with a low-fat diet. Fourteen children with LCHAD or TFP deficiency, 1-12 years of age at enrollment, were followed for 2-5 years. Three subjects with TFP β-subunit mutations had normal appearance of the posterior pole of the ocular fundi at enrollment and no changes over the course of the study. Eleven subjects who were homozygote and heterozygote for the common mutation, c.1528G > C, had no change to severe progression of atrophy of the choroid and retina with time. Of these, four subjects had marked to severe chorioretinopathy associated with high levels of plasma hydroxyacylcarnitines and decreased color, night and/or central vision during the study. The plasma level of long-chain 3-hydroxyacylcarnitines, metabolites that accumulate as a result of LCHAD and TFP deficiency, was found to be negatively correlated with maximum ERG amplitude (R max ) (p=0.0038, R 2 =0.62). In addition, subjects with sustained low plasma long-chain NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 3-hydroxyacylcarnitines maintained higher ERG amplitudes with time compared to subjects with chronically high 3-hydroxyacylcarnitines. Visual acuity, as determined with the VEP, appeared to increase with time on DHA supplementation (p=0.051) and there was a trend for a positive correlation with plasma DHA concentrations (p=0.075, R 2 =0.31). Thus, optimal dietary therapy as indicated by low plasma 3-hydroxyacylcarnitine and high plasma DHA concentrations was associated with retention of retinal function and visual acuity in children with LCHAD or TFP deficiency.

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Section: Discussionmentioning

confidence: 99%

Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency

Gillingham

Weleber

Neuringer

et al. 2005

Molecular Genetics and Metabolism

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“…As mentioned above, 7DHC is highly prone to oxidation (far more so than is cholesterol), and its oxysterol products are highly cytotoxic. Also, it is possible that 7DHC or its by-products may potentiate the (Fliesler and Anderson, 1983). It is interesting to note that cells in the inner nuclear layer (INL) appear relatively unaffected in all cases.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…docosahexaenoic acid), or visa versa. PUFA concentrations are exceptionally high in ROS membranes (Fliesler and Anderson, 1983). It is interesting to note that cells in the inner nuclear layer (INL) appear relatively unaffected in all cases.…”

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confidence: 93%

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Richards

Nagel

Fliesler

2006

Experimental Eye Research

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The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease presenting with multiple congenital anomalies, caused by a defect in cholesterol biosynthesis that results in abnormally elevated levels of 7-dehydrocholesterol (7DHC). Progressive retinal degeneration has been demonstrated in a rat model of SLOS, which is markedly exacerbated by intense light, far more so than occurs in normal albino rats under the same conditions. Herein, we demonstrate that, by six postnatal weeks, retinas in the SLOS rat model contain levels of lipid hydroperoxides (LPOs) comparable to those found in light-damaged albino rats (twice the normal steady-state levels), and that intense light exposure results in a three-fold elevation of LPOs with concomitant severe retinal degeneration. These results suggest a correlation between retinal degeneration and LPO levels. We propose that the presence of 7DHC in the SLOS rat retina potentiates LPO formation, and promotes the observed hypersensitivity to light-induced retinal degeneration. KeywordsAY9944; Smith-Lemli-Opitz syndrome; retina; degeneration; light damage; lipid hydroperoxide; rat Retinal degenerations resulting either from hereditary or exogenous causes are thought to entail molecular events that, in part, involve oxidative damage to lipids, proteins, and/or nucleic acids, resulting in cellular dysfunction and, ultimately, cell death. Such events are known to be potentiated by exposure to intense light (Organisciak and Winkler, 1994;Boulton et al., 2001;Glickman, 2002;Wenzel et al., 2005). Certain metabolic conditions result in the formation of pro-oxidant molecules, the presence of which can promote cellular degeneration and death. The Smith-Lemli-Opitz syndrome (SLOS) likely represents such a condition. SLOS, the first described 'multiple congenital anomalies syndrome ' (Smith et al., 1964; cf. Porter, 2000;Jira et al., 2003), is also the first member of a growing family of inborn errors of anabolic metabolism involving defective cholesterol biosynthesis (Kelley, 2000;Porter, 2003). SLOS specifically is due to a defect in 3β-hydroxysterol-Δ 7 -reductase (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005), resulting in abnormal and excessive accumulation of the cholesterol precursor, 7-dehydrocholesterol (7DHC) (Tint et al., 1994 cf. Fliesler, 2002).We have previously demonstrated a progressive retinal degeneration in a pharmacologically induced rat model of SLOS (Fliesler et al., 2004). More recently, we showed that intense light exposure markedly exacerbates that retinal degeneration, whereas treatment of rats with dimethylthiourea, a hydroxyl radical scavenger and anti-oxidant, prior to light exposure largely protects against the enhancement of degeneration (Vaughan et al., 2005), implicating a free radical mechanism in the degeneration. Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particu...

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“…Alternatively, long chain PUFAs (LCPUFAs) with 20 or more carbons can be obtained directly from the animal, and particularly the fish, components of the diet. The membrane phospholipids in brain contain high concentrations of the LCPUFA docosahexaenoic acid (DHA) [5], with highest levels observed in synaptic membranes [6,7], the growth cones of neurites [8,9] and rod outer segments of the retina [10,11]. Clinical and laboratory studies indicate that a number of neurodegenerative diseases involve cell membrane abnormalities which are associated with DHA deficiency [12][13][14][15], and that supplementation with DHA may offer protection against neuronal damage and cell death [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

Richardson

Wurtman

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The synthesis of phospholipids in mammalian cells is regulated by the availability of three critical precursor pools: those of choline, cytidine triphosphate and diacylglycerol. Diacylglycerols containing polyunsaturated fatty acids (PUFAs) apparently are preferentially utilized for phosphatide synthesis. PUFAs are known to play an important role in the development and function of mammalian brains. We therefore studied the effects of unsaturated, monounsaturated and polyunsaturated fatty acids on the overall rates of phospholipid biosynthesis in PC12 rat pheochromocytoma cells. Docosahexaenoic acid (DHA, 22:6n-3), eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (AA, 20:4n-6) all significantly stimulated the incorporation of 14 C-choline into total cellular phospholipids. In contrast, monounsaturated oleic acid (OA) and the unsaturated palmitic (PA) and stearic (SA) acids did not have this effect. The action of DHA was concentration-dependent between 5 and 50 μM; it became statistically significant by 3 hrs after DHA treatment and then increased over the ensuing 3 hours. DHA was preferentially incorporated into phosphatidylethanolamine (PE) and phosphatidylserine (PS), while AA predominated in phosphatidylcholine (PC).

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Chemistry and metabolism of lipids in the vertebrate retina

Cited by 918 publications

References 262 publications

Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency

Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

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