ARTICLE
Auteur(s) : Niyazi
Acar
Equipe de Recherche Œil et Nutrition, UMR1129 FLAVIC, INRA -
ENESAD - Université de Bourgogne, Dijon, France
For a long time, dietary fatty acids have only been considered as
the part of the lipid supply necessary for energy supply and tissue
growth. The evidence that some polyunsaturated fatty acids (PUFAs)
serve as indispensable dietary precursors for biologically active
molecules (such as eicosanoids) has given later a greater
significance to their study. As a consequence, increasing attention
has focused on the functions of omega-3 and omega-6 PUFAs in
different organs and particularly in neuronal tissues such as the
retina where omega-3 PUFAs are quantitatively important.
Omega-3 PUFAs in retinal structure and function
The structural organisation of the retina
The retina is a thin tissue, which lines the interior of the
posterior globe. Since it is embryologically derived from the
neural tube, the retina is considered as a peripheral extension of
the central nervous system. Histologically, the retina consists in
a superposition of different cell layers, in which retinal pigment
epithelial cells (RPE), photoreceptor cells (rods and cones),
bipolar cells and ganglion cells are of functional importance (figure 1). An
anatomical particularity exists between RPE cells and
photoreceptors consisting in deep invaginations of photoreceptor
outer segments into the extensive apical villous processes of RPE
cells, thus creating an intimate physical relationship between
these two cell types. The exchange of nutrients and gases between
the retina and the blood is accomplished through two independent
circulatory systems. The choroidal system, located between the
sclera and RPE cells, consists of an arborized network of
capillaries separated from the basal surface of the RPE by the
Bruch’s membrane. This blood supply serves the outer retinal layers
composed by RPE cells and photoreceptors. The second blood supply
enters the retina through the optic nerve head and serves as a
source of nutrients for all inner retinal layers, including bipolar
cells and ganglion cells.
The quantitative and functional importance of omega-3 PUFAs in
the retina
Lipids account for about one third of retinal dry weight. The major
lipid class within this tissue is represented by phospholipids.
Phospholipids can account for until 70% to 80% of total lipids in
some animal species [1]. Retinal phospholipids are mainly composed
by phosphatidyl-choline and phosphatidyl-ethanolamine whose levels
are of 47% and 31% of total phospholipids in human retina,
respectively. When regarding to the fatty acid composition of
retinal lipids, it appears that over 50% of total fatty acids are
unsaturated, of which PUFAs account for 60%. Docosahexaenoic acid
(DHA) is the most ubiquitous PUFA in the mammalian retina and is
present in up to one third of total fatty acids when considering
the whole retina and until up to 60% of total fatty acids within
the membrane of the photoreceptor outer segments [1].
The functional significance of this unique fatty acid
composition of photoreceptor membranes was extensively studied by
the group of Litman and Mitchell [2-6]. These authors have proved
that DHA-rich photoreceptor membranes display properties that
influence the photon capture by affecting the conformational change
of the rhodopsin protein in response to light absorption.
Particularly, they have shown that the activation of rhodopsin in
response to light was facilitated with increasing unsaturation of
the acyl-chain in membrane phospholipids (figure 2). These
properties are based on the 22 carbons and the 6 double bonds of
the DHA molecule conferring him biophysical and the biochemical
particularities that affect membrane fluidity and thickness.
The presence of DHA in mammalian retina appears to be remarkably
constant among species and strong conservation mechanisms exist
locally and systemically rendering the retinal fatty acid profile
resistant to changes by means of dietary manipulation. This is
probably why the attempts to deplete mammals such as rat and monkey
of retinal omega-3 fatty acids by short- or mid-term dietary
manipulations have had limited success [7-12]. Whereas other organs
exhibited severe depletion of PUFAs, only minor decreases in
retinal PUFAs were observed. In cases of chronic deprivations,
retinal DHA losses have been shown to give rise to functional
deficits (evaluated by electroretinography) [9, 11, 12] and reduced
visual acuity [7, 13].
The emerging concept about omega-3 PUFAs acting as metabolic
bioactivators
For some years, an increasing number of data have proved that
omega-3 PUFAs may act as metabolic bioactivators by regulating some
key factors involved in cellular processes such as gene expression,
oxidative stress, inflammation, cell signaling and apoptosis. Even
if all the concerned studies do not directly involve the retinal
tissue, these data have built a strong basis for the current and/or
future investigations about the functions of omega-3 PUFAs in the
retina. The available literature on this topic was extensively
reviewed and discussed by SanGiovanni and Chew [14]. Only the major
points are presented in this section.
Gene expression
The regulation of gene expression by omega-3 PUFAs can occur at
multiple levels. First, omega-3 PUFAs can operate at the
transcriptional level by binding to specific ligands that interact
with response elements in the promoter region of genes, then
affecting gene transcription. This was mainly demonstrated for DHA
that can bind nuclear receptors such as the Retinoid X receptor
(RXR) and alpha, beta and gamma isoforms of peroxisome
proliferator-activated receptor (PPAR) [15–17]. DHA may also act at
the post-transcriptional level beyond the synthesis of protein by
modifying the gene products formed [18]. Once mRNA is formed, DHA
can modify native mRNA processing, mRNA transport, and stability
and breakdown rates.
Redox balance and resistance to light damage
From a biochemical point of view, the nature of PUFAs (containing
from one to six unsaturations) and their presence into a
metabolically active place (exposed to light irradiation and/or
high levels of oxygen) would make very probable the formation of
oxidized lipids. This appears to be particularly true when
considering the high concentration of DHA in retinal photoreceptor
outer segments, which are continuously exposed to light
illumination. However, the data obtained in vitro and in vivo were
very controversial.
In vitro studies on model membranes or liposomes have generally
reported a higher susceptibility of PUFAs to peroxidation in
response to energy or oxygen exposure. Results from in vivo studies
were different. In rats, lower DHA status was associated with lower
susceptibility to acute white light exposition [19]. Moreover, rats
fed diets deficient in omega-3 PUFAs exhibited better structural
outcomes than rats fed alpha-linolenic acid-enriched diet after
intense green light illumination [20]. The relationships between
omega-3 PUFA or fish intake with reactive oxygen species biomarkers
was studied in human. In some cases, in vivo oxidation of was not
modified as a function of PUFA intake [21, 22] whereas it was
decreased in others [23]. Omega-3 PUFA intake at very high doses
was shown to operate as a pro-oxidant [24].
Inflammation
The potential implication of omega-3 PUFAs in the regulation of
inflammatory processes was the subject of numerous studies
(reviewed by [25]). PUFAs with 20 carbons are precursors of
biologically active mediators named “eicosanoids”. Eicosanoids are
composed by leukotrienes (LTs), prostaglandins (PGs) and
thromboxanes (TXs). Eicosanoids formed from omega-3 PUFAs are
derived from eicosapentaenoic acid (EPA, omega-3 series) and are
from series-5 for LTs and from series-3 for PGs and TXs.
Eicosanoids formed from EPA display anti-inflammatory properties.
In vitro studies on human cell lines have shown that omega-3 PUFAs
(through eicosanoids production) can decrease the expression of
TNF-alpha, IFN-gamma IL-1beta, IL-6 and IL-8, the production of
IL-2, the expression of surface antigen and the activation and
proliferation of T-lymphocytes. Most of these results were
confirmed in vivo in animals fed with diets enriched or deprived of
omega-3 PUFAs. Even if these results do not directly concern the
eye, one can assume that similar cells and/or proteins may be
targeted by omega-3 PUFAs during retinal inflammatory response.
Neovascularization
The evident relationships between retinal vascular and neural
structures (namely the shared radial orientation of blood vessels
and ganglion cell axons and the precise alignment of plexuses with
horizontal neurons and astrocytes) is a proof that the retinal
vascular anatomy is highly organized. This is probably the reason
why retinal neovascularization processes, which are characterized
by chaotically oriented and physiologically deficient vessels that
do not conform to neuronal organization, are often the cause of
loss of vision and eventually blindness in various retinal
disorders. Among these disorders, diabetic retinopathy (DR) and
age-related macular degeneration (AMD) are the most prevalent in
the Western World. For both diseases, adequate therapy is not
available to date, laser therapy being performed to physically
destroy new vessels and to stop their growing instead of preventing
their apparition. For a few years, a promising therapeutic for the
prevention of neovascularization processes is based on the
administration of anti-angiogenic agents such as inhibitors of
vascular endothelial growth factors (VEGFs). These ones were first
developed for anticancer medication before being used in eye
diseases. However, some important points about the safety or the
insufficient selectivity of these agents remain unclear. Consistent
evidences suggest that omega-3 PUFAs can exert anti-angiogenic
properties through the modulation of processes involved in
intracellular signalling, activation of transcription factors and
production of inflammatory mediators. The numerous studies
demonstrated the involvement of omega-3 PUFAs themselves, that of
their secondary metabolites (eicosanoids) or that of the enzymes of
their metabolism (cyclooxygenase, lipoxygenase).
The establishment of a functional vascular network requires the
regulation of the proliferation, the migration and the
differentiation of endothelial cells, the regulation of vascular
branching, the regulation of the remoulding of the extracellular
matrix in front of the sprouting vessel and the regulation of the
stabilization of the nascent blood vessels. Individual studies
proved that omega-3 PUFAs are able to i) prevent endothelial cell
activation, proliferation, migration as well as their tube forming
activity; ii) prevent vascular branching by reducing the expression
of adhesion molecules or integrins (such as VCAM-1, E-selectin,
ICAM-1); iii) influence tissue remodeling by affecting the activity
of matrix metalloproteinases (MMPs); iv) reduce the expression
and/or production of pro-angiogenic factors involved in vessel
stabilization such as VEGF, TGF-beta, TNF-alpha, FGF, PDGF,
angiogenin, angiotensin II, follistatin, IL-8 and leptin (reviewed
by [14]).
Cell survival
The rationale for suggesting that omega-3 PUFAs promote cell
survival is based on past studies showing that DHA promotes cell
survival following various stresses [14]. Recently, it was
demonstrated that these properties are not displayed by DHA itself
but by one of its metabolites named neuroprotectin D1 (NPD1)
(reviewed by [26]). In the retina, the biosynthesis of NPD1 from
DHA was demonstrated to occur in RPE cells. In addition to
counteract oxidative stress, NPD1 was shown to prevent apoptotic
DNA damage by up-regulating the anti-apoptotic proteins from the
Bcl-2 family (namely Bcl-2, Bcl-xL, Bfl-1/A1) and down-regulating
pro-apoptotic proteins from the Bax family (namely Bax, Bad, Bid,
Bik) [27].
Omega-3 PUFAs in human retinal diseases: example of AMD
The biochemical parameters on which omega-3 PUFAs may act are all
involved in several retinal diseases that manifest both vascular
and neuronal features. Within these diseases, AMD is probably the
most relevant since it is the leading cause of vision loss in
people aged of more than 65 years in western countries (30% of
people over 70 years). The physiopathology of AMD is very complex
and not yet fully understood. The current knowledge hypotheses that
some unknown events involving oxidative stress and inflammation
lead to RPE cell dysfunction in the central area of the retina
(macula). This dysfunction is the cause of an accumulation of cell
debris and metabolic products in the subretinal area, leading to
RPE cell degeneration followed by that of macular photoreceptors.
The consequence for the patient is a loss of central vision. In
some forms, the retinal tissue attempts to rescue macular cells by
promoting choroidal neovascularization, then enhancing the risk of
collateral damages such as haemorrhages. The risk factors of AMD
include the genetic background (polymorphism of ABCR and ApoE
genes), the oxidative stress (aging, smoking, exposition to light,
pigmentation) and the nutrient intake including omega-3 PUFAs.
A number of epidemiologic studies were performed to check the
prevalence of AMD in relation to omega-3 PUFAs or fish intake.
These studies, that were only observational and no interventional,
were in accordance by demonstrating a protective effect of omega-3
PUFA consumption regarding the prevalence and the progression of
AMD. Within these studies, the results from the Age Related Eye
Disease Study (AREDS) show that omega-3 PUFAs decrease the risk of
neovascular AMD (progression of AMD) by 40% when considering total
omega-3 PUFA intake (OR = 0.61 highest versus lowest quintile; 95%
CI: 0.41 - 0.90) and by 50% when considering DHA intake (OR = 0.54
highest versus lowest quintile; 95% CI: 0.36 - 0.80) (table 1) [28].
Table 1 Odd ratios for neovascular AMD by
energy-adjusted intake of omega-3 PUFAs (adapted from [28]).
|
Quintile
|
Cases with neovascular AMD
|
Cases without AMD
|
|
p trend
|
|
Alpha-linolenic acid
|
1
|
131
|
229
|
1 [reference]
|
0.82
|
|
2
|
137
|
220
|
0.93 (0.67-1.32)
|
|
|
3
|
129
|
226
|
0.90 (0.64-1.27)
|
|
|
4
|
127
|
229
|
0.96 (0.68-1.36)
|
|
|
5
|
133
|
211
|
1.02 (0.72-1.44)
|
|
|
|
|
|
|
|
Eicosapentaenoic acid (EPA)
|
1
|
158
|
208
|
1 [reference]
|
0.05
|
|
2
|
146
|
212
|
1.02 (0.74-1.43)
|
|
|
3
|
121
|
228
|
0.88 (0.62-1.24)
|
|
|
4
|
116
|
231
|
0.78 (0.55-1.10)
|
|
|
5
|
116
|
236
|
0.75 (0.52-1.08)
|
|
|
|
|
|
|
|
Docosahexaenoic acid (DHA)
|
1
|
163
|
198
|
1 [reference]
|
0.004
|
|
2
|
135
|
213
|
0.85 (0.61-1.20)
|
|
|
3
|
120
|
240
|
0.65 (0.45-0.93)
|
|
|
4
|
131
|
224
|
0.75 (0.52-1.08)
|
|
|
5
|
108
|
240
|
0.54 (0.36-0.80)
|
|
|
|
|
|
|
|
Total omega-3 PUFAs
|
1
|
163
|
206
|
1 [reference]
|
0.01
|
|
2
|
137
|
207
|
0.91 (0.65-1.27)
|
|
|
3
|
125
|
239
|
0.72 (0.51-1.02)
|
|
|
4
|
121
|
226
|
0.77 (0.54-1.10)
|
|
|
5
|
111
|
237
|
0.61 (0.41-0.90)
|
|
|
|
|
|
|
Conclusion
It is now well known that the tissue content in lipids can be
modified by the diet. This evidence is also true when considering
the relationships between dietary omega-3 PUFAs and retinal fatty
acid composition, even some specific strategies to protect this
tissue against dietary insufficiencies. Since on the other hand,
omega-3 PUFAs are known to be protective against of oxidative
stress, inflammation, cell death and abnormal vascularization, one
can hypothesize that their consumption would be beneficial against
retinal disorders displaying such characteristics. The first
epidemiological studies investigating the relationships between
dietary fatty acid consumption and ocular pathologies strongly
confirm this hypothesis.
References
1 Fliesler SJ, Anderson RE. Chemistry and metabolism of
lipids in the vertebrate retina. Prog Lipid Res 1983; 20: 79-131.
2 Litman BJ, Mitchell DC. A role for phospholipid
polyunsaturation in modulating membrane protein function. Lipids
1996; 31(suppl): S191-S197.
3 Litman BJ, Niu SL, Polozova A,
Mitchell DC. The role of docosahexaenoic acid containing
phospholipids in modulating G protein-coupled signalling pathways:
visual transduction. J Mol Neurosci 2001; 16: 237-42.
4 Mitchell DC, Niu SL, Litman BJ. Optimization of
receptor-G protein coupling by bilayer lipid composition I:
kinetics of rhodopsin-transducin binding. J Biol Chem 2001; 276:
42801-6.
5 Mitchell DC, Niu SL, Litman BJ. Enhancement of
G protein-coupled signalling by DHA phospholipids. Lipids 2003; 38:
437-43.
6 Niu SL, Mitchell DC, Litman BJ. Optimization of
receptor-G protein coupling by bilayer lipid composition II:
formation of metarhodopsin II-transducin complex. J Biol Chem 2001;
276: 42807-11.
7 Neuringer M, Connor WE, Van Petten C,
Barstad L. Dietary omega-3 fatty acid deficiency and visual
loss in infant rhesus monkey. J Clin Invest 1984; 73: 272-3.
8 Watanabe I, Kato M, Aonuma H, et al.
Effect of dietary alpha-linolenate/linoleate balance on the lipid
composition and electroretinographic responses in rats. Adv Biosci
1987; 62: 563-70.
9 Bourre JM, Francois M, Youyou A, et al.
The effects of dietary alpha-linolenic acid on the composition of
nerve membranes, enzymatic activity, amplitude of
electrophysiological parameters, resistance to poisons and
performance of learning tasks in rats. J Nutr 1989; 119:
1880-92.
10 Pawlosky RJ, Denkins Y, Ward G, Salem N.
Retinal and brain accretion of long-chain polyunsaturated fatty
acids in developing felines: the effects of corn oil-based maternal
diets. Am J Clin Nutr 1997; 65: 465-72.
11 Weisinger HS, Vingrys AJ, Sinclair AJ. The
effect of docosahexaenoic acid on the electroretinogram of the
guinea pig. Lipids 1996; 31: 65-70.
12 Weisinger HS, Vingrys AJ, Bui BV,
Sinclair AJ. Effects of dietary n-3 fatty acid deficiency and
repletion in the guinea pig retina. Invest Ophthalmol Vis Sci 1999;
40: 327-38.
13 Neuringer M, Connor WE, Lin DS,
Barstad L, Luck S. Biochemical and functional effects of
prenatal and postnatal omega 3 fatty acid deficiency on retina and
brain in rhesus monkeys. Proc Natl Acad Sci USA 1986; 83:
4021-5.
14 Sangiovanni JP, Chew EY. The role of omega-3
long-chain polyunsaturated fatty acids in health and disease of the
retina. Prog Retin Eye Res 2005; 24: 87-138.
15 De Urquiza AM, Liu S, Sjoberg M, et al.
Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse
brain. Science 2000; 290: 2140-4.
16 Lin Q, Ruuska SE, Shaw NS, Dong D,
Noy N. Ligand selectivity of the peroxisome
proliferator-activated receptor alpha. Biochemistry 1999; 35:
185-90.
17 Yu W, Bayona W, Kallen CB, et al.
Differential activation of peroxisomes proliferators-activated
receptors by eicosanoids. J Biol Chem 1995; 270: 23975-83.
18 Uauy R, Hofmann DR, Peirano P, Birch DG,
Birch EE. Essential fatty acids in visual and brain
development. Lipids 2001; 36: 885-95.
19 Bush RA, Reme CE, Malnoe A. Light damage in
the rat retina: the effect of dietary deprivation of N-3 fatty
acids on acute structural alterations. Exp Eye Res 1991; 53:
741-52.
20 Organisciak DT, Darrow RM, Jiang YL,
Blanks JC. Retinal light damage in rats with altered levels of
rod outer segment docosahexaenoate. Invest Ophthalmol Vis Sci 1996;
37: 2243-57.
21 Bonanome A, Biasia F, De Luca M, et al.
N-3 fatty acids do not enhance LDL susceptibility to oxidation in
hypertriacylglycerolemic hemodialyzed subjects. Am J Clin Nutr
1996; 63: 261-6.
22 Higdon JV, Liu J, Du SH, Morrow JD,
Ames BN, Wander RC. Supplementation of postmenopausal
women with fish oil rich in eicosapentaenoic acid and
docosahexaenoic acid is not associated with greater in vivo lipid
peroxidation compared with oils rich in oleate and linoleate as
assessed by plasma malondialdehyde and F(2)-isoprostanes. Am J Clin
Nutr 2000; 72: 714-22.
23 Ando M, Sanaka T, Nihei H. Eicosapentanoic acid reduces
plasma levels of remnant lipoproteins and prevents in vivo
peroxidation of LDL in dialysis patients. J. Am. Soc.
Nephrol.;10:2177–84.
24 Vericel E, Polette A, Bacot S, Calzada C, Lagarde M. Pro- and
antioxidant activities of docosahexaenoic acid on human blood
platelets. J. Thromb. Haemost.;1:566–72.
25 Calder PC. Polyunsaturated fatty acids, inflammation,
and immunity. Lipids 2001; 36: 1007-24.
26 Bazan NG. Cell survival matters: docosahexaenoic acid
signalling, neuroprotection and photoreceptors. Trends Neurosci
2006; 29: 263-71.
27 Mukherjee PK, Marcheselli VL, Serhan CN,
Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived
docosatriene protects human retinal pigment epithelial cells from
oxidative stress. Proc Natl Acad Sci USA 2004; 101: 8491-6.
28 Sangiovanni JP, Chew EY, Clemons TE,
et al., Age-Related EYE DISEASE STUDY RESEARCH GROUP. The
relationship of dietary lipid intake and age-related macular
degeneration in a case-control study: AREDS Report No. 20. Arch
Ophthalmol 2007; 125: 671-9.
|
Version imprimable
Version PDF
