Clinical Lipidology

ISSN: 1758-4299 (Print) 1758-4302 (Online) Journal homepage: http://www.tandfonline.com/loi/tlip20

Dual roles of polyunsaturated fatty acids in retinal

physiology and pathophysiology associated with
retinal degeneration

Masaki Tanito & Robert Anderson

To cite this article: Masaki Tanito & Robert Anderson (2009) Dual roles of polyunsaturated fatty
acids in retinal physiology and pathophysiology associated with retinal degeneration, Clinical
Lipidology, 4:6, 821-827

To link to this article: http://dx.doi.org/10.2217/clp.09.65

Copyright 2009 Future Medicine Ltd

Published online: 18 Jan 2017.

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 Review

Dual roles of polyunsaturated fatty acids in

retinal physiology and pathophysiology
associated with retinal degeneration
Retinas are highly enriched with long-chain polyunsaturated fatty acids (PUFAs). The reduction of docosahexenoic
acid in the photoreceptor outer segment membrane leads to a reduction in the electroretinographic response,
suggesting crucial roles for PUFAs in normal retinal physiology. Epidemiological studies suggest a correlation between
environmental light exposure and the development/progression of human retinal degenerations such as age-related
macular degeneration and retinitis pigmentosa. The double bonds in PUFAs could be target substrates to propagate
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photooxidative stress in photoreceptors. Light exposure to animals results in selective losses of photoreceptor and
retinal pigment epithelial cells and post-translational modifications of retinal proteins by 4‑hydroxynonenal and
4‑hydroxyhexenal. These end products of nonezymatic oxidation of n‑6 and n‑3 PUFAs, respectively, are likely to be
involved in the light-induced retinal degeneration. Low levels of 4-HNE generated by low levels of environmental light
exposure upregulate endogenous redox molecules such as thioreodoxin and thioreodoxin reductase via the nuclear-
factor E2-related factor 2/antioxidant-responsive element pathway in the retina, and confer retinal neuroprotection.
This paper highlights the dual roles of retinal PUFAs in cellular physiology and pathology.

KEYWORDS: 4-hydroxyhexenal n 4-hydroxynonenal n age-related macular degeneration Masaki Tanito1,† &

n docosahexaenoic acid n glutathione n light-induced retinal degeneration
n nuclear factor E2-related factor 2 n polyunsaturated fatty acid n thioredoxin
Fatty acids in the retina
n‑3 and n‑6 polyunsaturated fatty acids
(PUFAs), which contain two or more methylene
interrupted cis double bonds, are major families
of fatty acids in mammalian cells. n‑3 and n‑6
fatty acids are synthesized from ‘essential’ fatty
acids 18:3n‑3 and 18:2, respectively, via a series
of oxidation (desaturation) and chain elonga‑
tion reactions. Retinal membrane phospholipids
have the highest levels of PUFA of any tissue.
Of the phospholipids in retinal photoreceptors,
phosphatidylcholine (PC), phosphatidylethano­
lamine (PE), phosphatidylserine (PS) and
phospatidylinositol (PI) comprise 40–50%,
30–35%, 5–15% and 3–6%, respectively  [1] .
Docosahexaenoic acid (DHA; 22:6n‑3) is the
most abundant fatty acid in the retina and its
levels in rod outer segment (ROS) membrane
phospholipids reache 40–50% of the total fatty
acids [1] . ROS membranes also contain the
photopigment rhodopsin (Figure 1) . The largest
amounts of DHA are found in the PE, PS and
PC. Arachidonic acid (AA; 20:4n‑6) is the most
abundant n‑6 fatty acid in the retina, reaching
levels of 8% in the ROS. DHA and AA levels
are almost equivalent in the retinal microvessels,
Robert E Anderson2,3
†
Author for correspondence:
1
Department of
with each approximately 10% of the total fatty Ophthalmology, Shimane
acids [2] . The largest amounts of AA are found University Faculty of Medicine,
in the PC and PE. Enya 89–81, Izumo, Shimane
693–8501, Japan
Physiological roles of DHA in Tel.: +81 853 202 284
retinal function Fax: +81 853 202 278
n‑3  PUFA deprivation by n‑3-deficient diets tanito-oph@umin.ac.jp
produced only modest changes in retinal DHA 2
University of Oklahoma Health
levels, thus the retina retains DHA and other Sciences Center, OK, USA
n‑3 PUFAs [3] . More significant changes could 3
Dean A McGee Eye Institute,
be produced by feeding pregnant rats an n‑3- OK, USA
deficient diet in the last trimester of pregnancy
and throughout the nursing period and by con‑
tinuing to feed the weaning rats the same diet
for 10–12 weeks [4] . Under these conditions, the
levels of DHA in the ROS were reduced by half
and replaced by nearly equal amounts of 22:5n‑6.
Even further reductions were achieved by raising
several generations on an n‑3-deficient diet [5] .
The reduction of DHA in ROS membranes leads
to significant changes in the electroretinographic
(ERG), a noninvasive measure of retinal function
in response to a light flash. The ERG consists of
a cornea negative a-wave, which arises in photo­
receptor cells, and a cornea positive b-wave, which
is generated in the neural retina. DHA deficiency

10.2217/CLP.09.65 © 2009 Future Medicine Ltd Clin. Lipidol. (2009) 4(6), 821–827 ISSN 1758-4299 821
 Review | Tanito & Anderson
GCL
IPL
INL
OPL
ONL
RIS
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ROS
RPE
CH
100 µm SC
Figure 1. Normal structure of retina. Retinal
sections from a rat are shown.
CH: Choroid; GCL: Ganglion cell layer;
INL: Inner nuclear layer; IPL: Inner plexiform
layer; ONL: Outer nuclear layer; OPL: Outer
plexiform layer; RIS: Rod inner segment;
ROS: Rod outer segment; RPE: Retinal pigment
epithelium; SC: Sclera.
results in the reduction of ERG responses, espe‑
cially the a-wave amplitudes [6] . Reduced maximal
response amplitudes attributed to n‑3 deficiency
have also been observed in guinea pigs [7] and
monkeys [8] , and in n‑3-deficient preterm human
infants [9] . Low blood levels of DHA have been
reported in patients with retinitis pigmentosa
(RP) [10,11] and low ROS DHA levels were found
in several different animal models of human reti‑
nal degenerations [12–14] . n‑3 deficiency has been
shown to reduce rhodopsin activation, to reduce
and delay rhodopsin-transducin coupling, and
to decrease cGMP-phosphodiesterase activity in
biochemical assays [15] .
Light stress & retinal degeneration
Epidemiological studies have suggested that
excessive light may enhance the progression and
severity of age-related macular degeneration
(AMD) and some forms of RP [16,17] . Hirakawa et
al. measured facial wrinkle length, which is con‑
sidered to be associated with a history of sunlight
exposure, in age-related maculopathy (ARM)
822 Clin. Lipidol. (2009) 4(6)
patients [18] . They found that facial wrinkling
was more severe in late ARM patients than in
early ARM patients, suggesting lifetime exposure
to sunlight is an important factor in the progres‑
sion of late ARM. Acute light exposure to rats
and mice causes selective losses of photoreceptor
and retinal pigment epithelial (RPE) cells [19] . The
apoptotic pathway, the common fate of photore‑
ceptors in RP and AMD, is the main pathway of
light-induced cell death [20] . Previous studies have
suggested that oxidant stress plays a major role in
retinal degenerations, including AMD [21,22] and
diabetic retino­pathy [23,24] . Intense light exposure
causes lipid peroxidation of retinal tissues  [25]
and oxidative stress is likely to be involved in the
pathogenesis of light-induced retinal damage [26] .
Thus, the use of light-induced damage in rodents
is a suitable model system to study retinal degen‑
eration and other retinal pathologies related to
oxidative stress [27] . It is important to note that
the susceptibility of retinal damage is differ‑
ent between animal species. In general, albino
animals are more easily damaged by light than
pigmented animals, and albino rats are more sus‑
ceptible to retina light damage than albino mice.
Exposure to white fluorescent light at 2700 lux
for 6 h causes devastating apoptotic photorecep‑
tor cell loss in albino rats raised in a dim cyclic
light environment [28] ; whereas exposure of white
fluorescent light at 8000 lux for 2 h only promotes
an oxidative stress in pigmented mice [29] .
Fatty acids as a molecular target of
photooxidative stress
Current data suggest that free radicals formed
during oxidative stress can directly attack criti‑
cal biomolecules including PUFAs, and initiate
free-radical chain reactions that result in lipid per‑
oxidation in cellular membranes. This chain reac‑
tion acts as an amplifier for the generation of lipid
radical species, causing PUFA degradation into a
variety of oxidized products, including aldehydes.
Thus, methylene interrupted double bonds in
PUFAs are target substrates to propagate oxidative
stress in photoreceptors. Some of these aldehydes
have been shown to be extremely reactive and can
potentially damage intra- and extracellular mol‑
ecules located some distance from the initial site
of free-radical attack as aldehydes are relatively
longer lived than free radicals [30,31] . Damaging
aldehydes include 4-hydroxyalkenals, such as
4‑hydroxynonenal (4‑HNE) and 4‑hydroxyhex‑
enal (4‑HHE). These are a, b-unsaturated alde‑
hydes that are end products of lipid peroxidation
of PUFAs. 4‑HNE is formed from n‑6 PUFAs
future science group
 Dual role of polyunsaturated fatty acids associated with retinal degeneration
such as linoleic acid and AA [32] , and 4‑HHE is
formed from n‑3 PUFAs such as DHA, eicosap‑
entaenoic acid and linolenic acid  [33] , via several
nonenzymatic steps. These highly reactive alde‑
hydes can react readily with histidine, cysteine or
lysine residues of proteins, leading to the forma‑
tion of stable Michael adducts with a hemi-acetal
structure [34] . These aldehydes exhibit a variety
of cytopathological effects such as inhibition of
enzyme activity; inhibition of protein, RNA and
DNA  synthesis; cell cycle arrest; and apopto‑
sis  [30] . Thus, it has been recognized that reac‑
tive aldehydes can exert cytotoxicity due to their
facile reactivity with proteins [35] . Formation of
protein modifications by 4‑HNE may be used as
an indicator for assessing the effect of antioxidants
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against retinal light damage [29,36,37] . When mice
were exposed to a light stress of 3000 lux for 24 h
– the outer nuclear layer (ONL) thickness – a
measure of the number of surviving photorecep‑
tors, was reduced; a- and b-wave amplitudes of
the ERG were lower and the number of apoptotic
photoreceptor cells, measured by TUNEL stain‑
ing, was greater in the mice with lower n6:n3
ratios and higher DHA levels in ROS [38] , sug‑
gesting a positive correlation between the level of
DHA and the vulnerability of the retina to photo-
oxidative stress. Immunohistochemical staining
of aldehyde-modified proteins was immediately
observed in the ONL of albino rat retinas and
3 h after light exposure; the retinal location of
these proteins corresponded well with the loca‑
tions that showed increased TUNEL staining at
24 h and severely decreased ONL thickness at
7 days after exposure. Thus, the post-translational
modifications of proteins by these aldehydes are
an early event that precedes apoptosis and subse‑
quent photo­receptor cell loss [39] . However, in a rat
model of diabetes, it is reported that dietary DHA
does not necessarily promote lipid peroxidation
in the retina even under high oxidative stress [40] .
Subretinal accumulation of drusen is a
major risk factor for the development of AMD
(Figure  2) . Drusen, which contains esterified
cholesterol-rich; and ApoB‑containing lipopro‑
tein particles are constitutively produced by the
RPE [41] and are thought to be fatty waste products
from the photoreceptor and other retinal cells. A
proteomic approach on damaging light-exposed
retinal specimens from rats found that intense
light exposure increased 4‑HNE protein modi‑
fications on specific retinal proteins from several
functional categories, including energy metabo‑
lism, glycolysis, chaperone, photo­transduction
and RNA processing [42] . Many of these proteins
future science group
| Review
are common among accumulated proteins found
in drusen from monkey [43] and human eyes [44] .
These data strongly support the idea that drusen
may be formed by subretinal/RPE accumulation
of degenerated macromolecules such as proteins
and lipids, and that photooxidation of fatty
acids in p­hotoreceptor cells is triggering these
p­athological steps.
Light adaptation neuroprotection
phenomenon in the retina
Compared with animals raised in dim cyclic
light (5  lux), albino mice and rats raised in
bright cyclic light (300–800  lux) were pro‑
tected from light (1700–3000 lux for 24–72 h)-
induced photoreceptor cell apoptosis [45,46] ,
suggesting that a light adaptation neuropro‑
tection phenomenon exists (Figure 3) . Thus,
environmental light may regulate the cellular
or tissue tolerance to photoreceptor cell dam‑
age induced by a forthcoming more intense
light exposure. The levels of DHA relative to
palmitic acid is 6.5 in ROS of rats raised in
dim (<10 lux) light environment and only 0.6
in bright (400 lux) light, this is accompanied
by shorter ROS, lower rhodopsin concentration
and altered rhodopsin regeneration rates [46] .
*
*
Figure 2. Human macular degeneration.
(A) Fundus photograph and (B) optical
coherence tomography images of human
macular degeneration show intense subretinal
accumulations of yellowish–white-colored
drusen (A) and elevation of retinal pigment
epithelium layer (B, asterisks). Arrows indicates
scanning direction.
www.futuremedicine.com 823
 Review | Tanito & Anderson
5 lux cyclic light-reared
INL
ONL
0.5 mm
5 lux cyclic light-reared + 3000 lux for 24 h
INL
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400 lux cyclic light-reared
INL
ONL
400 lux cyclic light-reared + 3000 lux for 24h
INL
ONL
Figure 3. Environmental light-induced neuroprotection. Representative retinal
sections from rats born and raised in dim cyclic (5 lux, 12 h on/12 h off) light
(A & B) or bright cyclic (400 lux, 12 h on/12 h off) light (C & D). Some animals
were exposed to intense (3000 lux for 24 h) light after rearing (B & D). Note the
severe loss of rod nuclei (ONL) in the dim-reared, intense light-exposed retina (B).
INL: Inner nuclear layer; ONL: Outer nuclear layer.
The fatty acid composition of inherited retinal
degeneration models chemically resembles the
membranes from the animals raised in bright
cyclic light [13] . Albino rats have the ability to
adapt to environmental light in order to catch a
constant number of photons per day – a ‘photo‑
stasis’ phenomenon [47] . Thus, control of photon
capture and the efficacy of visual transduction
through control of the ROS DHA level may be
survival mechanisms in retina against harmful
bright light [48] .
824 Clin. Lipidol. (2009) 4(6)
Compared with dim cyclic light-reared rats,
those reared in bright cyclic light had greater
retinal levels of endogenous antioxidant enzymes
glutathione (GSH) peroxidase [49] , GSH reduc‑
tase [49] , GSH S‑transferase [49] , thioredoxin (Trx;
2.4‑fold) [50] , Trx reductase (TrxR; 2.9‑fold) [50]
and proteins modified by 4‑HNE (1.5‑fold) [50] .
In addition, bright cyclic light-reared rats had
more nuclear translocation of transcription fac‑
tor Nrf2 (2.2‑fold) and DNA-binding activity
of Nrf2, small Maf and cJun to the antioxidant-
responsive element (ARE) [50] . These findings
demonstrate the plasticity of the retina and
support a role for lipid peroxidation in light
stress‑induced retinal degeneration.
What is the cellular signal that leads to upreg‑
ulation of endogenous defense mechanisms?
Treatment of 661W cells (immortalized mouse
cone cells) with 4‑HNE caused a dose-depen‑
dent cell death. However, pretreatment with a
sublethal dose of 4‑HNE protected against sub­
sequent H2O2-induced cell damage [45] . Treatment
with 4‑HNE upregulated cellular Trx, TrxR and
heme oxygenase (HO)‑1 levels, as well as the
DNA‑binding activity of Nrf2, small Maf and
cJun to the ARE. Downregulation of Nrf2 using
RNA interference technology diminished 4‑HNE-
mediated upregulation of Trx and TrxR, but did
not affect the upregulation of HO‑1 by 4‑HNE.
Cytoprotection by 4‑HNE pretreatment against
H2O2-induced cell damage was not observed
in 661W cells with a silenced Nrf2 gene. These
results suggest that upregulation of the Trx system
by 4‑HNE via the Nrf2–ARE pathway is involved
in the molecular mechanism of the retinal neuro­
protection phenomenon [50] . Thus, in the early
stages of cellular stress, the generation of 4‑HNE
at low concentrations has an important role in cell
signal transduction and gene e­xpression, including
Nrf2‑ARE-driven gene regulation [51,52] .
Conclusion
Environmental light exposure may affect the
development and progression of human retinal
degenerations such as AMD and RP. The use of
light exposure in rodents is a suitable model sys‑
tem to study retinal degenerations and other reti‑
nal pathologies related to oxidant stress. PUFAs
including DHA play crucial roles in normal
retinal physiology. On the other hand, double
bonds in PUFAs are target substrates to propa‑
gate oxidative stress in photoreceptors. Products
of oxidatively degraded PUFAs, including 4‑HNE
and 4‑HHE, decorate specific classes of retinal
proteins including those involved in energy
future science group
 Dual role of polyunsaturated fatty acids associated with retinal degeneration
metabolism/glycolysis, chaperone activities, photo
and signal transduction, and RNA processing.
These decorations could be related to the initiation
of the inflammatory response that occurs in mac‑
ular degeneration. Data support the hypothesis
that the accumulation of 4‑HNE is involved in the
retinal induction of redox-regulating m­olecules
such as Trx and TrxR via the Nrf2–ARE pathway
in rats that are reared in bright cyclic light and that
this is a molecular mechanism of the light-induced
retinal neuroprotection phenomenon.
In light of our present knowledge, we sug‑
gest that neurons requiring high levels of PUFA,
including DHA and AA, to support various com‑
ponents of cell function react to oxidant stress in
two ways. Stress causes release of DHA, which
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| Review
mimics an adaptive response mediated by bright
cyclic light. Accordingly, modulations of the Trx
system via Nrf2–ARE pathway activation could
be a molecular target to prevent photooxidative
stress-related retinal diseases such as AMD, RP
and photic maculopathy. Clinical trials applying
compounds mimicking adaptive responses need
to be conducted.
The roles of DHA in the retina are potentially
conflicting in the literature. DHA is implicated
in retinal degenerations using its capacity to act
as an oxidation substrate. Crabb et al. found an
increased decoration of proteins in Bruch’s mem‑
brane preparations from human eyes with AMD
and not in age-matched controls [44] , by using a
carboxyethylpyrrole (CEP) antibody that recog‑

is converted into bioactive docosanoid(s) such as
neuroprotectin D1, which then act at several levels
to provide neuroprotection. Simultaneously, the
oxidant stress converts some PUFAs to 4‑HNE,
4‑HHE, and other toxic products, which upregu‑
late other neuroprotective pathways. These path‑
ways, and possibly others yet to be defined, are
important in protecting post-mitotic cells, which
once destroyed, cannot be regenerated.
Future perspective
Administration of Trx inducers, such as the
antigastric ulcer drug geranylgeranylacetone or
broccoli component sulforaphane, effectively
upregulates endogenous Trx in retinal tis‑
sues  [37,53] . Thus, the use of these compounds
nizes protein adducts formed by peroxidation of
DHA. Injections of CEP-albumin in mice led to
the generation of anti-CEP antibodies and the
development of a retinal phenotype that resem‑
bled human AMD [54] . Cell culture studies have
demonstrated that DHA protects retinal [55]
and RPE [56] cells from oxidant stress-induced
apoptosis, perhaps by acting as a precursor of the
neuroprotective eicosanoid neuroprotectin D1
(NPD1) [56] . A diet rich in n‑3 fatty acids was
shown to be inversely associated with the risk
for AMD [57–59] . On the basis of these and other
studies, the recently undertaken Age-Related
Eye Disease Study (AREDS) II clinical trial will
hopefully better define the role of DHA in the
development and progression of AMD.

Executive summary
Fatty acids in the retina
„„ Docosahexaenoic acid (DHA) and arachidonic acid are major fatty acids of neural retina and vascular tissue.
„„ In rod outer segment (ROS) membranes, DHA reaches the highest body concentrations per unit weight.

Physiological roles of DHA on retinal function

„„ The retina tenaciously retains DHA and other n‑3 polyunsaturated fatty acids during n‑3 deprivation.

„„ Reduction in DHA in ROS membranes leads to significant changes in the reduction of electroretinographic responses, especially

a-wave amplitudes.
Light stress & retinal degeneration
„„ Environmental light may enhance progression and severity of age-related macular degeneration and some forms of retinitis pigmentosa.

„„ Acute light exposure to rats and mice causes selective losses of photoreceptor and retinal pigment epithelial cells.

„„ Light-induced damage in rodents is a suitable model system to study retinal degeneration.

Fatty acids as a molecular target of photooxidative stress

„„ Double bonds in PUFAs are target substrates to propagate oxidative stress in photoreceptors.

„„ 4‑hydroxyalkenals such as 4‑hydroxynonenal (4‑HNE) and 4‑hydroxyhexenal (4‑HHE) are end products of lipid peroxidation of n‑6 and

n‑3 PUFAs, respectively.
„„ Post-translational modifications of proteins by 4‑HNE and 4‑HHE are an early event that precedes apoptosis and subsequent

photoreceptor cell loss after light exposure.

Light adaptation neuroprotection phenomenon in retina
„„ ‘Photostasis’ through a control of ROS DHA level may be a survival mechanism in the retina against harmful bright light.

„„ 4‑HNE at low concentrations upregulates endogenous redox molecules such as thioreodoxin and thioreodoxin reductase via the nuclear-

factor-E2-related factor 2 (Nrf2)/antioxidant-responsive element pathway.

„„ The 4‑HNE/Nrf2/ARE/Trx pathway is likely to be involved in the light-induced retinal neuroprotection phenomenon.

future science group www.futuremedicine.com 825

 Review | Tanito & Anderson
Financial & competing
interests disclosure
This work was supported by grants from the NIH
(EY00871, EY04149, EY12190 and RR17703) and
the Foundation Fighting Blindness to REA, and an
unrestricted grant from Research to Prevent
Blindness. The authors have no other relevant affili-
ations or financial involvement with any organiza-
tion or entity with a financial interest in or financial
conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the
p­roduction of this manuscript.
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