Lipid homeostasis plays a critical role in inherited and acquired retinal diseases

Abstract

The photoreceptor layer of the retina converts light stimuli into electrical signals and transmits them to the visual cortex for image processing. Photoreceptor cells rely on a constant supply of nutrients, including lipids, to replenish their high demand of membrane remodelling. Dysregulated retinal lipid homeostasis results in ectopic lipid deposition that triggers oxidative stress, inflammatory response, mitochondrial dysfunction, and impaired signal transduction, thereby contributing to the pathogenesis of retinal degeneration in several eye diseases. In this review, we discuss the importance of lipid homeostasis in the normal functioning of the retina and how dysregulation in this process due to genetic or acquired factors manifests in various retinal pathologies. We summarize potential strategies to mitigate the pathological effects of retinal diseases.

A review summarizes the importance of lipid homeostasis in the normal functioning of the retina and how dysregulation in this process due to genetic or acquired factors manifests in various retinal pathologies.

Introduction

The retina converts light stimulus into electrical signals and transmits it into the visual cortex for image processing. The vertebrate retina is a highly stratified tissue comprising of primarily six neuronal types having specialized functions: light-responsive photoreceptors (rods and cones), bipolar, ganglion, amacrine, horizontal, and interplexiform cells, plus glial cells (Astrocytes, microglia, and Muller cells). The retinal pigment epithelium (RPE) is a densely packed monolayer of polarized epithelial cells rich in melanin pigment that lies between the retina and choroid (Fig. 1A). The basal side of RPE faces the Bruch’s membrane (BrM), whereas apical side having microvilli is exposed toward the photoreceptor outer segment (OS) increasing the surface area in contact with the OS thereby enhancing regulation^1,2. The microenvironment of the retina is separated from the systemic circulation by a dynamic blood-retina barrier (BRB) that is actively involved in the supply of necessary nutrients and to prevent harmful substances from reaching the light sensitive neural tissue. The BRB is composed of an outer BRB (oBRB) and an inner BRB (iBRB)³. The oBRB consists of choroid, BrM, and the RPE, that selectively allows passive diffusion based on size and blocking large molecule diffusion⁴. The BrM prevents migration of inflammatory cells, provides support to the RPE and act as a cushion for physical force stress⁵. The tight junctions (TJs) at the apical surface of RPE formed by Claudin and Occludin family of proteins is important to maintain the integrity of oBRB by separating the choriocapillaris and sub-retinal space⁶. The iBRB comprises of endothelial cells lining the retinal vasculature supplying the inner retinal layers that penetrates retina at three plexuses: nerve fibre layer, inner plexiform layer (IPL), and outer plexiform layer (OPL)⁷. These vessels vascularize the retina upto the OPL, with the photoreceptor cell layer remaining avascular. Structurally, the iBRB comprises of neurovascular unit (NVU), similar to blood-brain barrier (BBB), consisting of retinal vascular endothelial cells, surrounded by pericytes, glial cells, astrocytes, Müller cells and microglia⁸. The iBRB facilitates the transport of molecules, ions, water and cells from systemic circulation into the retina through transcellular and paracellular routes⁹. Unlike small lipophilic molecules that can freely diffuse from the endothelial cells, large lipophilic molecules, along with hydrophilic molecules, and ions cross the iBRB via ATP-dependent transport mechanisms, including receptor/carrier/ion-mediated transport and efflux pumps¹⁰. However, most of the transport at oBRB occurs through transcellular route due to increased resistance encountered paracellularly¹¹.

Fig. 1. Organization of retinal pigment epithelium cell and photoreceptor cells in healthy and pathological retina.

A Healthy retina with normal photoreceptor cells (rods and cones) that interact with apical microvilli region of retinal pigment epithelium (RPE) cells. Underlying RPE is intact Bruch’s membrane and normal blood vessels in the choroid plexus. Me melanosomes, M mitochondria, N nucleus, ER endoplasmic reticulum, G Golgi apparatus, LD lipid droplet, L phagolysosome. B Morphological changes in RPE and photoreceptor cells in a pathological retina. Illustration depicting degeneration of RPE cells that manifest in photoreceptor cells degeneration. Gross morphology defect in rods and cones with reduced cell density. Loss of melanin pigment containing melanosomes in RPE cells, hence affecting stray light absorption. Accumulation of LDs in various retinal degeneration diseases affecting membrane remodelling and energy production. Decreased mitochondrial number resulting in impaired redox homeostasis and energy production. Accumulation of lipofuscin due to abnormal lipid metabolism. Increased thickness of Bruch’s membrane with accumulation of abnormal fats and proteins into “drusen” particles in the subretinal space. Enhanced pathological neovascularization is seen, resulting in damage to RPE cells and inner retinal cells. C Schematic depiction of the classical visual cycle. The cycle starts with the transport of all-trans-retinol in the RPE cells. Interphotoreceptor retinol binding protein (IRBP) binds and solubilizes all-trans-retinol within the interphotoreceptor matrix and directs it to the endoplasmic reticulum (ER) of RPE cells where lecithin:retinol acyltransferase (LRAT) converts it into all-trans-retinyl esters (RE), a storage form of vitamin A that is deposited into lipid droplets (LDs) together with other neutral lipids, triacylglycerol (TAG) and cholesterol esters (CE). The key enzyme RPE65 converts all-trans-retinyl esters to 11-cis-retinol, which is further oxidized to 11-cis-retinal by the enzyme 11-cis-retinol dehydrogenase (11cRDH). 11-cis-retinal is bound by IRBP and further transported to photoreceptor cells where it binds to the protein opsin within the outer segment (OS) disc membrane to form the complex rhodopsin (light sensitive pigment). When rhodopsin absorbs light, the 11-cis-retinal is converted to all-trans-retinal, triggering a conformation change that activates phototransduction cascade. The phototransduction cascade involves activation of transducing (a G-protein), activation of phosphodiesterase (PDE) and conversion of cGMP to GMP within photoreceptor cells, closure of ion channels, and hyperpolarization of photoreceptor cells. The formed 11-trans-retinal is released and reduced to all-trans-retinol by atRDH enzyme and is transported to RPE cells by IRBP to continue the cycle.

The RPE provides nutrients, including vitamin A (retinol) derivatives, docosahexaenoic acid (DHA), an essential omega-3 fatty acid to photoreceptors, ensuring visual cycle homeostasis and performs crucial role in phagocytosis and recycling of constantly shedded OS of photoreceptor cells². Light-sensitive pigments, rhodopsin and photopsin, found in rods and cones, enable eyes to respond to dim or bright light respectively¹. Cones are further subdivided into two (three in primates) spectral types based on wavelength maxima. Moreover, there are ~10 different types of bipolar cells, including ON and OFF types that fine tunes retinal circuitry¹². Similarly, ~20 types of amacrine cells and ~10 distinct subtypes of ganglion cells¹². Strikingly, photoreceptors cells loose ~10% of membrane mass each day as its turned over via shedding of the “disk” membrane at distal tip (proximal to RPE); however, compensatory amount of new membranes is being added at the base of the OS¹³. Hence, the demand on the retina to replenish its lipids, particularly phospholipids and cholesterol for growing new membranes, is enormous. Therefore, lipid metabolism plays a critical role in maintaining homeostasis of various retinal cell types.

Lipid homeostasis is vital for energy storage, maintaining membrane dynamics, acting as signalling molecules and overall cellular function, thereby influencing a myriad of physiological processes, including health of retina. Photoreceptor cells rely on a constant supply of lipids from RPE cells to replenish their high demand of membrane remodelling. Almost one-third of retina dry weight comprises of lipids¹⁴. Cells have evolved mechanisms for regulated lipid synthesis, uptake, transport, storage and its degradation depending on extracellular milieu. Dysregulated lipid metabolism manifests in several human pathologies such as lipodystrophy, obesity, type-2 diabetes, insulin resistance, cancer, and neuronal diseases¹⁵. Dyslipidemia has been strongly associated with pathogenesis and progression of several retinal diseases; diabetic retinopathy (DR)¹⁶, age-related macular degeneration (AMD), retinal microvasculature abnormalities, and corneal disorders^17,18 (Fig. 1B). Moreover, disrupted lipid homeostasis results in lipid accumulation and/or ectopic lipid deposition that often triggers oxidative cell death via lipid peroxidation and ferroptosis, resulting in formation of toxic lipid species that adversely affects functioning of several organ systems¹⁹. In the eye, lipid peroxidation has been implicated in the pathophysiology of several ocular diseases such as AMD, glaucoma, cataract, and DR. Further, free radicals catalyze peroxidation of long chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (AA) and DHA resulting in production of metabolites including isoprostanes and/or neuroprostanes that exert toxicological effects on ocular tissues²⁰. Therefore, a better understanding of association between defects in lipid metabolism and disease progression can provide insights and treatment strategies for related diseases.

In this review, we discuss the importance of lipid homeostasis in the retina to ensure proper visual functioning and how dysregulation in this process manifests in various retinal pathologies, while exploring potential therapeutic strategies for mitigating ocular diseases.

Visual cycle

The visual/retinoid cycle is the biochemical pathway that regenerates light sensitive molecules essential for vision when a photon of light strikes retina and the light energy is converted into an electrical signal and transmitted via the optic nerve to the brain. This phototransduction is mediated by a G protein coupled receptor (GPCR) opsin, that contains 11-cis-retinal chromphore²¹. In the presence of light 11-cis-retinal undergoes photoisomerization to an all-trans-retinal, resulting in a conformational change in opsin-GPCR that activates downstream signal transduction cascade leading to closure of c-GMP gated cation channels and hyperpolarization of photoreceptor cells^22,23. Following isomerization, all-trans-retinal is released from the opsin on the luminal side of the photoreceptor OS disc membrane, it binds to phosphatidylethanolamine, resulting in formation of N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), a toxic by-product²⁴. N-retinylidene-PE is flipped to the cytoplasmic side of OS disc membrane by the ATP-binding cassette subfamily transporter A4 (ABCA4) where it dissociates into all-trans-retinal and PE²⁴. All-trans-retinal is reduced to an all-trans-retinol by an enzyme called all-trans-retinol dehydrogenase (atRDH) in the cytoplasm and is exported into the subretinal space (Fig. 1C). All-trans-retinol binds to interphotoreceptor retinoid-binding protein (IRBP) and diffuses into the RPE cells. In the RPE, all-trans-retinol is esterified by endoplasmic reticulum (ER)-resident enzyme, lecithin-retinol acyltransferase (LRAT) to retinyl-esters (RE) that are deposited into morphologically unique lipid droplet (LD) structures called retinosomes²⁵ (Figs. 1A, 2A). Retinosomes contain predominantly REs together with other lipids such as triacylglycerol (TAG), cholesterol esters (CE), and cholesterol²⁶. Upon demand, REs are hydrolysed and isomerized to 11-cis-retinol by an ER localized isomerohydrolase, RPE65 (also called Isomerase I), which is further oxidized to 11-cis-retinal by 11-cis-retinol dehydrogenase (11cRDH) enzyme before returning back to photoreceptors cells with the help of IRBP, where it combines with opsins, to regenerate rhodopsin (Fig. 1C)^21,27,28. More than 100 mutations in RPE65 have been implicated in retinal diseases, including both autosomal dominant and autosomal recessive forms, thereby underscoring the importance of RPE65 in visual chromophore homeostasis for continued visual function^29,30.

Fig. 2. Lipid trafficking between retinal pigment epithelium cell and photoreceptor cells.

A Model depicting biogenesis of lipid droplets (LDs)/retinosomes from endoplasmic reticulum (ER) in the RPE cells. Enzymes responsible for the synthesis of neutral lipids, triacylglycerol (TAG) and cholesterol esters (CE) are ER localized. Diacylglycerol:acyltransferase (DGAT) produce TAG, whereas acyl-CoA:cholesterol acyltransferase (ACAT) synthesize CE. TAG and DAG accumulate as lens-like structures that is sequestered by ER transmembrane protein seipin resulting in formation of nascent lipid droplets (LDs) that grows and matures within the cytoplasm. Various LD biogenesis factors facilitate the birth of LDs at seipin defined ER sites. The ER localized enzyme lecithin:retinol acyltransferase (LRAT) converts all-trans-retinol into all-trans-retinyl esters (RE), a storage form of vitamin A to be deposited into LDs. The enzyme RPE65 is a hydrolase that converts RE to 11-cis-retinol a critical step in the functioning of the visual cycle. Mutations in the RPE65 gene leads to development of various retinal pathologies including Leber’s congenital amaurosis (LCA), and retinitis pigmentosa (RP). B Dynamic lipid transport between RPE and photoreceptor cells. Serum lipids are internalized within the RPE by a set of membrane transporters that localize at the basal membrane region of RPE cells. Several lipoprotein trafficking receptors localize at basal membrane of RPE cells; low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), cluster of differentiation 36 (CD36), scavenger receptor class B, member 1 (SCARB1), and major facilitator superfamily domain containing protein 2a (MFSD2A), a transporter that specifically uptakes DHA. Once inside the RPE cells, these lipids bind to fatty acid binding proteins (FABP) or other lipid binding proteins for intracellular transport. Lipoproteins, cholesterol and fatty acids are digested within the lysosomal compartment, released and delivered to the ER for further interconversion into neutral lipids, TAG, and CE and packaged for storage into LDs. Lipids are further transported to the apical surface to be trafficked into photoreceptors. The apical surface handles lipid trafficking in opposite directions: lipid supply from RPE to photoreceptors, while outer segment (OS) uptake and phagocytosis by the RPE microvilli, facilitated by specific transporters. Membrane transporters, ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), are involved in the efflux of cholesterol and phospholipids towards the extracellular milieu. CD36 and MERTK regulate the phagocytosis of shedded OS membranes into RPE. Recycled lipids from metabolized OS are returned back to photoreceptor cells. Adiponectin receptor 1 (ADIPOR1) and membrane-type frizzled-related protein (MFRP) regulate lipid transport to maintain homeostasis; however, their precise mode of action is not completely known. The membrane transporter ABCA4 localizes to disc rims of OS of photoreceptor cells and regulates the removal of toxic waste products generated during phototransduction upon light sensing.

Lipid droplets play an essential role in sequestering retinol intermediates

LDs serve as reservoirs of storage neutral lipids (NLs), TAG and CE and play crucial role in energy and lipid homeostasis, biogenesis of membranes, and synthesis of signalling molecules. The architecture of LDs comprises of a core of NLs surrounded by a phospholipid monolayer decorated with a specific set of LD-resident proteins having roles of lipogeneis, lipolysis, and regulation of LD interaction with other organelles mediated via contact sites. LDs biogenesis occurs in the ER, where NL synthesizing enzymes catalyze production of TAG and CE within the bilayer membrane resulting into lens-like structures that eventually grows into nascent LDs emerging toward the cytoplasm while remaining associated with the outer phospholipid leaflet of the ER^31,32 (Fig. 2A). Dysregulated LD biogenesis manifests in various pathological conditions such as lipodystrophy, obesity, type-2 diabetes, insulin resistance, and cancer^15,33,34. Growing evidence supports the model in which seipin (Sei1 in yeast), an ER transmembrane protein defines discrete ER subdomains at which LD biogenesis factors are recruited in a step-wise manner for the assembly of LDs^35,36. Mutations in human seipin manifests in severe form of congenital generalized lipodystrophy (CGL) where patients experience near absence of fat tissue, along with neurological problems collectively known as seipinopathies^37,38. The role of seipin in nucleation of TAG-rich LDs is well described³⁹; however, whether seipin plays a role in the biogenesis of RE containing retinosomes remains largely unexplored (Fig. 2A). A recent study explored the requirement of seipin in the formation of RE-containing LDs in yeast model system. It has been shown that yeast mutants devoid of NL synthesizing enzymes and hence lacking any detectable LDs, when express human LRAT in the presence of exogenously supplied retinol, begin to form LDs⁴⁰. However, in the absence of seipin, upon stimulation of RE formation resulted in LDs being formed of aberrant size distribution, a typical LD morphology defect phenotype of seipin null mutant, indicating a defective RE-rich LD biogenesis⁴⁰. How seipin promotes sequestration and formation of LDs containing distinct class of NLs, such as RE awaits future exploration (Fig. 2A). More recently, it has been demonstrated in vitro using model membranes and cultured cells that formation of CE-rich LDs occurs at seipin defined ER sites, and presence of TAG promotes its nucleation⁴¹. Hence, future studies should investigate how seipin might be important for the formation of retinosomes in RPE cells and what factors might be crucial for this process.

The regression of LDs is regulated by several members of the perilipin (PAT) family. NLs within LDs is degraded by the sequential action of lipases: adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 (ATGL/PNPLA2), hormone sensitive lipase (HSL), and monoglyceride lipase (MGL), thereby liberating free fatty acids⁴². It has been shown that PNPLA2 associates with LDs in hepatic stellate cells and possesses retinyl ester hydrolase (REH) activity in vitro⁴³. Moreover, REH activity of PNPLA2 in the RPE cells is essential for efficient mobilization of RE for visual pigment regeneration⁴⁴. Absence of PNPLA2 results in significant accumulation of LDs within RPE, and a delayed 11-cis-retinal regeneration resulting in delayed electroretinography (ERG) response together with failure to adapt in dark conditions compared to controls⁴⁴. Hence, LDs/retinosomes play a crucial role in the regeneration of visual cycle chromophore for maintaining normal vision.

Lipid and lipoproteins homeostasis between RPE and photoreceptors

The transport of hydrophobic lipid molecules within the blood is mediated by lipoprotein particles, a variety of specialized protein carriers of varying size and density encapsulating lipid cargo such as cholesterol, CE, and TAG in a hydrophilic shell. Major types include (in the order of size); high-density lipoproteins (HDL), low-density lipoproteins (LDL), intermediate-, and very-low-density lipoproteins (IDL and VLDL), and largest and lowest density chylomicrons (CM)⁴⁵. The RPE plays a pivotal role in facilitating major metabolite exchange at the oBRB, including lipids within the outer retina⁴⁶. Lipoprotein uptake within the RPE is facilitated by specific transporters localized to the basal membranes of the RPE layer, such as LDL receptor (LDLR)⁴⁷, VLDL receptor (VLDLR)⁴⁸, scavenger receptor class B member 1 (SCARB1/SR-BI)⁴⁹, cluster of differentiation 36 (CD36)⁵⁰, and Major Facilitator Superfamily Domain containing protein 2a (MFSD2A), a transmembrane protein highly expressed in the BBB endothelium and in the RPE cells that transports lysophosphatidylcholine (lysoPC) to the brain and photoreceptor cells^51,52 (Fig. 2B). DHA is primarily transported in a lysoPC form, is essential for brain development, cognitive functions, establishment of BBB and photoreceptor OS formation⁵². Mutation in Mfsd2a results in impairment of BBB and lethal microcephaly⁵¹. Interestingly, TJ barrier prevents diffusion of membrane proteins between the basal and apical surface of RPE, hence both surfaces selectively differ in their receptor composition and lipid uptake properties. The basolateral face of RPE is enriched in LDLR, lack of which in mice results in overaccumulation of lipids in the BrM and gradual photoreceptor degeneration⁵³. This indicates that LDL particle derived lipids constitute an important source for efficient functioning of RPE cells. Similarly, lack of VLDLR results in decreased levels of FA in the retina⁴⁸. Absence of Mfsd2a results in severe depletion of DHA levels in the mouse retina that manifests in slow progressive retinal degeneration phenotype⁵⁴.

Upon internalization, lipids interact with various lipid binding proteins such as fatty acid binding proteins (FABP), are metabolized and/or stored into LDs/retinosomes. Subsequently, lipids are transported to the apical surface for further flux toward the neural retina. The apical surface of RPE regulates two processes of opposing directionality: supplying lipids to the photoreceptor cells and concomitant selective phagocytosis of OS membranes derived from photoreceptors, each facilitated by specialized transporters/membrane proteins. The ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) which utilize ATP to facilitate efflux of various lipids, such as cholesterol and phospholipids into the extracellular matrix to lipophilic acceptor proteins⁵⁵, whereas Mer tyrosine kinase (MERTK), integrin, CD36 regulate OS phagocytosis⁵⁶. The ingested OS within the phagolysosomes are metabolized and key components are recycled and returned back to the photoreceptor cells. Remarkably, RPE specific deletion of both the transporters, ABCA1, and ABCG1, results in blockage of lipid trafficking and overaccumulation of LDs within the RPE cells that promotes inflammatory response and gradual retinal degeneration⁵⁷. Moreover, the apical membrane is highly enriched in two other transporters, adiponectin receptor 1 (ADIPOR1) and membrane-type frizzled-related protein (MFRP), lack of which results in significant alteration in mouse retinal lipid profile⁵⁸, and a gradual photoreceptor loss⁵⁹. ADIPOR1 exhibits ceramidase activity leading to release of sphingosine and FFA⁶⁰. Lack of AdipoR1 gene in mice results in accumulation of ceramides in the retina, that leads to degenerative phenotype mimicking clinical features of retinitis pigmentosa¹. More recently, ADIPOR1 has been shown to modulate the levels of ELOVL2, an essential enzyme in the elongation of PUFA converting C20/C22 into C24 precursors required for DHA biosynthesis and VLC-PUFA, hence photoreceptor degeneration in AdipoR1 KO mice might primarily be affecting DHA metabolism rather than its transport into the retina⁶¹. Unlike the RPE, both rods and cones lack MFSD2A; however, express ADIPOR1 at the highest level in the retina promoting DHA uptake and conversion into LC-PUFA in the inner segment (IS) of rod cells, mostly localizing to the OS of photoreceptor cells^59,62. AdipoR1 KO mice shows an altered PUFA profile in the retina and RPE, with decreased ω3 LC-PUFAs and an increased ω6 PUFAs⁶³. Lack of AdipoR1 impairs peroxisome proliferator-activated receptor α (PPARα) signaling, which is important for fatty acid metabolism, thereby affecting PUFA transport and oxidation in the retina and RPE, a condition rescued by inhibiting ceramide production, hence, alleviating photoreceptor degeneration⁶³. Expression of ELOVL2 reduces with age due to promoter hypermethylation, resulting in lower levels of VLC-PUFA, reduced retinal thickness and impaired visual function^64,65. Variants in the ELOVL2 gene have been associated with increased progression to intermediate stage AMD. Interestingly, intravitreal supplementation of ELOVL2 VLC-PUFA products in aged mice resulted in improved retinal responses to visual stimuli for up to 4 weeks and exhibited a partial rejuvenation of transcriptomic and lipidomic profile in old mice resembling younger retinas, highlighting VLC-PUFA supplementation as a potentially therapeutic approach and ELOVL2 as a potential target for mitigating age-related vision loss⁶⁵.

MFRP, a highly specialized transmembrane protein of RPE cells, is essential for ocular development, mutations in which are associated with autosomal recessive nonsyndromic nanophthalmos, that leads to hyperopia and early onset of retinitis pigmentosa⁶⁶. Recent work has suggested MFRP as a molecular hub in organizing apical surface of RPE cells where it acts as a scaffold for the localization of ADIPOR1, and Inward Rectifier Potassium Channel 13 (KCNJ13) proteins⁶⁶. MFRP is essential for the transport of DHA into the retina, lack of which results in DHA accumulation, indicating crucial role of MFRP in DHA metabolism. Moreover, MFRP regulates the expression levels of LRAT and RPE65 enzymes, absence of which leads to reduced levels of 11-cis retinal and altered visual cycle kinetics⁶⁶. MFRP binds to lipids including phosphatidylserine (PS) and phosphatidylinositol-4-phosphate (PI(4)P)⁶⁶. PS is important for RPE-retina interface where it facilitates initiation of photoreceptor OS phagocytosis, indicating role of MFRP in this process⁶⁶. Hence, MFRP constitutes an essential interaction hub within the apical membrane of RPE cells where it coordinates protein trafficking and subcellular localization, thereby modulating lipid homeostasis within the entire retina⁶⁶.

Cholesterol homeostasis in retina

Cholesterol is a vital constituent of central nervous system including retina forming a major component of cellular membranes and exist mostly in the unesterified form in nerve myelin sheath, which enwraps axons and plasma membrane of both neurons and glial cells. The slightly amphipathic structure of cholesterol due to hydrophobic non-polar body and a hydrophilic polar head (OH hydroxyl group) enables cholesterol to integrate in cellular membranes. Cholesterol plays an important role in modulating physico-chemical properties of cell membranes, such as fluidity and ion permeability and thus modulates the function of resident proteins and regulates signal transduction, membrane trafficking and ligand binding⁶⁷. Cholesterol facilitates several aspects of neurotransmission, including formation of synapses and synaptic plasticity, which are crucial for memory and learning^68,69. Although the brain contains the highest concentration of cholesterol, it is isolated from systemic circulating lipoproteins due to the presence of BBB, thereby relying exclusively on de novo synthesis^70,71. Under steady-state conditions, endogenously synthesized cholesterol is balanced by excretion of 24S-hydroxycholesterol (24S-OHC) synthesized by CYP46A1, a cytochrome P-450 enzyme, via the BBB^72,73. 24S-OHC, a major oxysterol of brain and retina has been shown to affect viability of neurons in vitro⁷⁴ and facilitate neuronal signaling and synaptic plasticity⁷⁵. Oxysterols also act as ligands for Liver X receptors (LXR), a class of nuclear transcription factors that regulate expression of cholesterol metabolism genes, fatty acid metabolism and inflammation⁷⁶. Dysregulated brain cholesterol homeostasis is associated with several neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease⁷¹. A great detail of cholesterol homeostasis in brain has been described previously [for review see refs. ^68,70,73].

In contrast, retinal cholesterol homeostasis involves a delicate balance of de novo synthesis mainly in Muller glial cells, uptake from plasma lipoproteins via the BRB, unlike impermeable BBB, and efflux mechanisms⁷⁷. Cholesterol is found in all layers of the retina, mostly in its free form⁷⁸, however an impaired cholesterol homeostasis results in its accumulation in specific layers and is implicated in retinal diseases, including age-related macular degeneration (AMD)⁷⁹. A hallmark feature of AMD is the deposition of cholesterol on either side of the RPE, including the BrM, resulting in lipid-rich deposits (drusen)⁷⁹. Previous GWAS (Genome Wide Association Study) studies have identified variants associated with AMD located within the genes encoding proteins involved in cholesterol metabolism⁸⁰. Elegant studies have demonstrated the endogenous production of cholesterol upon intravitreal injection of deuterated substrate in the rat retina^81,82, with recent estimation representing ~70% of retinal biosynthesis⁸³. Studies in mouse, monkey and human retinas have shown the presence of lipoprotein receptors at the basal surface of RPE cells facing choriocapillaries; LDLR, scavenger receptor class B member 1 (SCARB1/SR-BI), CD36, regulating lipoprotein uptake^49,84,85. Both the apical and basal sides of RPE expresses ABCA1 transporter that regulates efflux of cholesterol resulting in formation of HDL particles. HDL particles further mature by the action of LCAT (lecithin:cholesterol acyltransferase) and CETP (cholesterol ester transfer protein). HDL-like particles could potentially cross the BRB and reach the systemic circulation to be further metabolized in the liver. Abca1 KO mice exhibits increased accumulation of intracellular cholesterol indicating crucial role of this transporter in cholesterol efflux from retinal cells⁸⁶. Cholesterol can also be excreted from the retina in the form of oxysterols, the major two being 24S-OHC and 3b-hydroxy-5-cholestenoic acid (27-COOH) a product of CYP27A1 enzyme that can easily cross the BRB.

Lipid metabolism disruption in retinal diseases

A systematic metabolic dysfunction results in dyslipidemia that impairs functioning of eye (reviewed in refs. ^1,87). Dyslipidemia encompasses both hyper- and hypo- levels of circulating lipids such as TAG, cholesterol, LDL, HDL, and polyunsaturated fatty acids (PUFAs). Dysregulated lipid homeostasis contributes to the pathogenesis of retinal dysfunction in several eye diseases.

Stargardt disease (STGD)

Stargardt disease type 1(STGD1) is an inherited autosomal recessive juvenile eye disease with a prevalence of 1 in 10,000 people. STGD is caused primarily due to mutation in ABCA4 gene, an ATP-binding cassette transporter superfamily, located on the OS of photoreceptor cells that encodes transmembrane receptor for transporting all-trans retinal from inside of photoreceptor disc into the cytoplasm after phototransduction to be converted into retinol, hence ensuring proper functioning of the visual cycle^88,89. One of the by-products formed after phototransduction is N-retinylidene-PE. In healthy retina functional ABCA4 helps to clear this by-product, thereby preventing its accumulation. However, mutated ABCA4 protein does not function efficiently leading to accumulation of toxic retinal substance called lipofuscin, rich in component called A2E⁹⁰. Lipofuscin, a yellow fatty material deposit is a mixture of lipid-containing residues that accumulate as abnormal lipid metabolism by-products within the RPE cells due to inefficient processing and removal⁹¹. It causes loss of central vision due to deposition of lipofuscin pigment in the macula region⁹². Since only central vision is impaired, patient do retain peripheral vision. Lipofuscin deposition leads to atrophy of the macular RPE and neuroepithelium⁹³. This results in toxicity of retinal cells, leading to death of photoreceptor cells, thereby resulting in progressive vision loss observed in STGD. Similarly, Stargardt type 3 disease (STGD3) is caused by three independent mutations in the gene ELOVL4, which encodes for elongase of very long chain fatty acids-4 and is inherited in an autosomal dominant pattern^94,95. Mutant ELOVL4 causes juvenile macular degeneration with progressive degeneration of the macula and peripheral retina^95,96. WT EVOLV4 is localized to the ER membrane of rod cells, Inner Segment (IS). However, all the mutations lead to a truncated ELOVL4 protein lacking a C-terminal di-lysine motif for ER retention, resulting in mislocalization of mutant ELOVL4 via the Golgi to OS disc membranes⁹⁷. This results in impaired synthesis of very long-chain C28-C36 fatty acids (VLC-PUFA) and ER stress that leads to photoreceptor cell death⁹⁸. Deficiency of VLC-PUFA having C28-C36 acyl resides may play an important role in the pathogenesis of STGD3 disease as C28-C36 acyl phosphatidylcholine (PCs) are required for the construction, function, and maintenance of photoreceptor OS where it strongly binds to rhodopsin and facilitate phototransduction⁹⁹. Absence of sufficient quantities of VLC-PUFA eventually results in photoreceptor cell death and retinal degeneration. Moreover, lack of VLC-PUFA might impair the production of elovanoids (ELV), bioactive lipid mediators that have protective function in RPE cells undergoing uncompensated oxidative stress by enhancing expression of pro-survival proteins¹⁰⁰.

Zellweger spectrum disorders (ZSD)

Zellweger spectrum disorders (ZSSD) are a group of autosomal recessive inherited disorders due to mutations in PEX genes affecting biogenesis of peroxisomes resulting in peroxisomal lipid metabolic imbalance¹⁰¹. Lack of functional peroxisomes results in impairment of hydrolysis of very long- or long chain fatty acids (VLCFAs) to medium- or short-chain fatty acids that are further metabolized in mitochondria. Bi-allelic mutations in one of the 13 PEX genes can lead to ZSD, with the most common mutations found in PEX1 and PEX6 accounting for more than 70% of cases¹⁰². PEX1 and PEX6 genes encode for members of AAA family of ATPases (ATPases with diverse cellular activities) forming a heterohexameric ring complex with three PEX1 and three PEX6 subunits alternating in a ring, anchored to the peroxisomal membrane via the docking protein PEX26 and are essential for receptor recycling from the peroxisomal membrane back to the cytosol¹⁰³. Mutation in PEX1/PEX6 results in export defect of PEX5, a matrix protein essential for import of peroxisomal matrix proteins¹⁰⁴. This results in accumulation of VLCFA in peroxisomes, thereby impairing mitochondrial functioning and hence abnormal levels of saturated and unsaturated FA accumulate¹⁰⁵. ZSD patients have severely compromised nervous system that manifests in RP, optic atrophy, corneal opacification, cataract, and glaucoma¹⁰⁶. DHA treatment maintains visual acuity and mitigates effects of peroxisomal biogenesis disorders in patients¹⁰⁷.

Gaucher disease, Faber’s disease, and Sandhoff’s disease

Amongst the lipid storage disorders, Gaucher disease, Faber’s disease, and Sandhoff’s disease are rare inherited lysosomal storage disorders that cause harmful accumulation of lipids in many of the organs including retina. Gaucher disease is caused by the deficiency of an enzyme ß-glucosidase (lysosomal glucocerebrosidase) due to mutation in GBA gene (most commonly L444P) and hence an inability to cleave glucocerebroside leading to build-up of gluosylsphingosine. It manifests in retinal degeneration, pigmented retinal lesions, and intra-retinal white dots¹⁰⁸. Faber’s disease is caused by mutation in ASAH1 gene that encodes acid-ceramidase enzyme, hence resulting in harmful accumulation of ceramides in various tissues including retina. Mice models of Faber’s disease show progressive retinal pathologies, including inflammation, retinal dysplasia, build-up of ceramides and other sphingolipids that result in severe vision impairment¹⁰⁹. Similarly, Sandhoff’s disease is caused by variants in hexosaminidase-B gene (HEXB) resulting in toxic accumulation of sphingolipids in the lysosomes of neuronal cells, affecting neuronal degradation and vision impairment¹¹⁰.

Smith-Lemli Opitz syndrome

Smith-lemli Opitz Syndrome (SLOS) is an autosomal recessive disease caused by mutation in both copies of DHCR7 gene that encodes 7-dehydrocholesterol reductase. The deficiency of this enzyme affects cholesterol metabolism that leads to toxic accumulation of 7-dehydrocholesterol (7-DHC), an intermediate in cholesterol biosynthesis thereby causing deficiency in total cholesterol levels. Symptoms include growth restriction, microcephaly (small head size), heart defects, malformation of hand and feet, and impaired brain and eye functioning¹¹¹. A deficiency in cholesterol levels might interfere in several cellular processes since cholesterol is a major lipid component of cellular membranes such as myelin in neurons, and lipid rafts that play pivotal role in signal transduction. Lack of cholesterol might also interfere with production of bile acids, steroid hormones, oxysterol, and neuroactive steroids. Mouse models of SLOS have revealed that deficiency of cholesterol affects the fluidity of rods OS membrane and impairs membrane lipid unsaturation thereby perturbing retinal functions such as rhodopsin regeneration that leads to retinal degeneration and defective visual function¹¹².

Retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by progressive loss of vision due to degeneration of photoreceptors. Patients typically experience tunnel vision (loss of peripheral vision) and night blindness due to loss of rod cells^113,114. In later stages, cones become affected leading to loss of central vision, hence patients have difficulty in reading and recognizing faces. RP is the most common form of genetically inherited retinal disease with a prevalence of 1 in 3000¹¹⁵. Genetically, RP displays all three forms of Mendelian Inheritance: autosomal dominant, autosomal recessive, and X-linked including mitochondrial inheritance modes¹¹⁶. Until now, ~280 genes have been identified that are implicated in one or the other form of inherited retinal disease, with several genes involved in lipid metabolism^{115,117–119}. The A346P missense mutation (alanine to proline substitution at codon 346) in the rhodopsin gene (RHO) interferes with regeneration of photoreceptors. Autosomal recessive mutation leads to truncated rhodopsin that results in loss of photoreceptor cells, poor peripheral vision, and diminished central vision that eventually leads to blindness^120,121. In addition, mutations in RPE65 gene also accounts for about ~2% of RP patients¹²¹. Mutation in gene encoding microsomal triglyceride transfer protein (MTTP) causes abetalipoproteinemia, a rare autosomal recessive disorder that causes a form of RP¹²². The MTTP gene codes for the larger subunit of the heterodimeric microsomal triglyceride transfer protein (MTP), that partners with protein disulfide isomerase (PDI). MTP protein complex is crucial for the biogenesis and secretion of apolipoprotein B-containing lipoprotein particles that occurs in the ER lumen of enterocytes and hepatocytes¹²³. Mutations in MTTP result in impaired lipoprotein formation, affects absorption and transport of fats, essential fatty acids and fat-soluble vitamins, particularly vitamin A and E^123,124. Prolonged deficiency of vitamin A and E might inhibit the normal functioning of neuronal and photoreceptor cells in the retina resulting in degeneration, and later onset of pigmentary changes throughout the fundus mimicking RP^125,126.

Previous studies have reported low levels of DHA in the retina of rodent models of RP^127,128, and in the blood of patients with RP^129,130. DHA is an essential lipid for the formation and remodelling of OS membranes, lack of which results in disordered disc morphology in photoreceptor cells¹³¹. DHA promotes rhodopsin activation and regulates its localization to OS, deficiency of which results in redistribution of rhodopsin in the rod cell body contributing to degenerative process in the retina¹³². The retina of rd10 mice, a model of RP showed a marked reduction in total fatty acids by 30% compared to WT retina¹³³. Lipidomics analysis has shown significant reduction in the levels of several short-chain and long-chain fatty acids together with monounsaturated fatty acids (MUFA) and PUFA (n-3 and n-6) in dystrophic retina compared to control¹³³. Reduced levels of myristic acid, a short-chain fatty acid involved in myristoylation of proteins, might perturb the interaction of proteins with lipid bilayers in photoreceptors. Two such proteins, Recoverin and GCAP-2, have role in phototransduction pathway, are myristoylated that facilitates their binding to the OS disc membrane in presence of high concentration of Ca^2+ 134. Consistent with decreased levels of myristic acid in the retina of rd10 animals, it might affect the interaction of proteins with the membranes, thereby impairing activation of photoreceptor proteins and phototransduction cascade in the diseased mice¹³³.

Diabetic retinopathy

Diabetic retinopathy (DR) results from complication of chronic diabetes (both type-1 and type-2) due to long-term effects of high blood sugar levels that damage blood vessels in the retina. DR is characterized by progressive retinal degeneration, neovascularization, and vision loss, a leading cause of blindness in working-age people¹³⁵. Globally, the number of DR patients is projected to increase to over 190 million by 2030¹³⁶. Early stages are asymptomatic; however, as the disease advances, patients experience blurry vision, faded colours, difficulty seeing at night, and dark spots in vision¹³⁷. In the initial non-proliferative DR (NPDR), blood vessels start to leak; however, in later advanced proliferative DR (PDR) stage, fragile neovasculature start to grow and hence causes severe vision impairment¹³⁷. In DR, neural metabolic demand drives neovascularization. In diabetic mice photoreceptor cells having higher density of mitochondria result in oxidative stress and inflammation, that triggers retinal vasculature damage in DR¹³⁸. The progression of DR is much faster in diabetic patients having dyslipidemia¹³⁹. Dyslipidemia strongly correlates with reduced retinal blood flow, thus resulting in thinning of retinal nerve fibres and ganglion cell layer¹⁴⁰. Elevated levels of serum apolipoprotein B (apoB) have been shown to be associated with the onset and severity of DR, whereas apoA-I/apoA-II may serve protective roles^141–143. During DR pathogenesis, modified LDL, with highly oxidized glycated-LDL (HOG-LDL) is taken up by the retinal cells, that exacerbates DR progression, thereby inducing caspase activation, mitochondrial dysfunction, and apoptosis in retinal capillary pericytes¹⁴⁴.

Oxysterols produced within the retina are activating ligands for LXR. LXR activation results in expression of ABCA1, ABCG1, and ApoE, genes that regulate efflux of cholesterol from RPE and retinal endothelial cells¹⁴⁵. LXR acts as a molecular sensor that when active suppresses NF-kB mediated inflammatory genes and prevents oxidative stress¹⁴⁶. LXR activity is further modulated by acetylation status, where nutrient sensing deacetylase, SIRT1 (Sirtuin 1) increases LXR activity. It has been shown that both the regulators, SIRT1 and LXR were downregulated in diabetic human retinal samples and type-2 diabetes animal model¹⁴⁷. Moreover, in diabetes the BRB gets compromised, leading to nonspecific entry of cholesterol, that results in reduced expression of LXR and reduction in cholesterol efflux activity that manifests in increased cholesterol accumulation in the retina. Activation of LXR restores cholesterol efflux from retinal cells, decreases inflammation, inhibits pro-inflammatory macrophage infiltration and ameliorates lipid accumulation and drusen-like deposits thereby preventing DR like pathology^146,147. Targeting LXR with N, N-dimethyl-3β-hydroxy-cholenamide (DMHCA), a selective LXR agonist upregulates cholesterol efflux via ABCA1 without modulating TAG biosynthesis has been show to correct retinal and BrM dysfunction, thereby restoring retinal homeostasis and hence acts as a promising therapeutic approach in DR¹⁴⁸.

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that heterodimerize with retinoid X receptor (RXR), an obligate binding partner, to regulate target gene expression levels by interacting with DNA response element within specific promoter region¹⁴⁹. PPARs control a myriad of biological processes, including adipogenesis, cell proliferation and differentiation, glucose and lipid metabolism, inflammation, angiogenesis, and immune function and hence are implicated in variety of diseases, including diabetic, cardiovascular, cancer, neurodegenerative, and ocular disease¹⁵⁰. Growing evidence suggests impaired RXR signaling is involved in neuronal stress and inflammation in several neuropathological conditions, including Parkinson’s, glaucoma, multiple sclerosis, Alzheimer’s and stroke¹⁵¹. PPAR isoforms (PPARα, PPARβ/δ, and PPARγ) are expressed in the retinal endothelial cells, choriocapillaris, and RPE cells, however its levels have been shown to be reduced in DR^152,153. Studies have shown protective role of activating PPARs in retinal diseases, including DR by mitigating retinal neurodegeneration and vascular damage¹⁵⁴. Reduced PPARα levels in diabetic retina lead to retinal inflammation and neovascularization in DR; however, activation of PPARα has an anti-inflammatory and anti-apoptotic effect in diabetic animal models by inhibiting NF-κB signaling^152,155. PPARα agonist such as fenofibrate significantly ameliorates DR microvascular complications such as retinal inflammation, vascular leakage, and apoptosis resulting in pericyte loss and neuroglial dysfunction^156,157. PPARα knockout abrogated the protective effect of fenofibrate against diabetes-induced retinal pericyte loss¹⁵⁶. Diabetic human and mouse retina expresses reduced levels of RXR, the activation of which using RXR agonist mitigates DR progression¹⁵⁸.

Unlike control retina that is enriched in omega-3 PUFA (EPA and DHA) with reduced levels of omega-6 PUFA (arachidonic acid), DR shifts the balance toward lower levels of omega-3 PUFA and higher levels of omega-6 PUFA¹⁴⁵. This results in shift of oxidized fatty acid products derived from omega-3 PUFA such as resolvins and protectins, found to have protective role by dampening inflammatory signals, to omega-6PUFA derived proinflammatory monooxygenase (MOX), lipoxygenase (LOX), and cyclooxygenase (COX) oxidized lipid mediators that further contribute to the pathogenesis of DR¹⁴⁵. Previous studies have shown dysregulated ceramide metabolism in DR^159,160. Metabolic imbalances in diabetes cause a shift in sphingolipid metabolism, resulting in increased level of short-chain proinflammatory and pro-apoptotic ceramides (C-16) produced from sphingomyelins by acid sphingomyelinase (ASM), and a reduced long-chain protective VLC-ceramides (C-26) in the retina, leading to retinal endothelial cell damage in DR¹⁶¹. Moreover, pro-inflammatory cytokines (TNF alpha, IL-1 beta) induced by diabetes trigger formation of ceramide-rich platforms (CRPs) in the plasma membrane of retinal vascular endothelial cells, leading to increased inflammatory signaling, endothelial cell apoptosis, retinal vascular dysfunction and leakage^161,162. Inhibiting ceramide production by targeting ASM, or using anti-ceramide antibodies offers strategy to prevent or reverse damage in NPDR and PDR^161,162. For DR complications, lipid-lowering therapy offers a potential treatment approach. Increased consumption of PUFA compared to unsaturated FA mitigates severity of DR complications. Diet including fish oil and omega-3 LC-PUFA in mice models of early DR preserves retinal neuronal function¹⁶³.

Age-related macular degeneration (AMD)

The human macula is critical for the sharpest and most detailed central vision. Fovea centralis is a small depression within the macula that contains predominantly cones, essential for colour and high acuity vision, surrounded by rod dominated para-fovea. Age-related macular degeneration (AMD) is a degenerative pathology that causes progressive damage to the macular region of retina and is the most common cause of irreversible loss of central vision along with widespread RPE cell death with significant photoreceptor loss in elderly people¹⁶⁴. Globally, the number of people with AMD is projected to increase to over 288 million by 2040¹⁶⁴. AMD is of two types: dry (late dry AMD or Geographic atrophy-GA) or exudative (wet AMD or neovascular AMD), based on the absence or presence of pathological blood vessels that invades from the choroid into the photoreceptor layer^165,166. Dry AMD is the most common form, where extracellular yellowish deposits of lipids and proteins accumulate in the subretinal space known as “drusen”¹⁶⁷. Although the precise mechanism is still being investigated, the BrM thickens due to presence of oxidized lipids, inflammatory debris that precedes drusen build up¹⁶⁷. Moreover, the old dying retinal cells are not being replaced, hence it slows down the trafficking of nutrients and removal of waste materials between RPE and choroidal vessels resulting in RPE dysfunction¹⁶⁸. Wet AMD patients experience choroidal neovascularization (CNV), in which immature blood vessels in the choroid expand below the RPE layer toward the outer retina, resulting in hemorrhage and plasma exudation. Late stage wet AMD further evolve into fibrotic scarring, RPE detachment and result in severe acute blindness¹⁶⁹.

Lipid metabolism dysfunction has been implicated in the pathology of AMD. Genome-wide association studies have uncovered several lipid metabolism genes associated with AMD susceptibility, including cholesterol efflux transporter ABCA1, cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase C (LIPC), and apolipoprotein E (APOE)¹⁷⁰. An impaired cholesterol efflux via ABCA1 transporter in mouse RPE or subretinal macrophages induces lipid accumulation that progresses into retinal degeneration⁵⁷. LXR expression in the human RPE decreases with age, resulting in reduced cholesterol efflux hence acts as a crucial factor in the development of dry AMD¹⁴⁶. Mice devoid of LXR exhibit dry AMD features, including deposition of extracellular oxidized lipids, disrupted BrM, and sub-RPE deposits¹⁴⁶. ApoE is an important protein for transporting cholesterol and other lipids across cell membranes and is highly expressed in the RPE cells. Deletion of ApoE results in increased plasma levels of TAG and cholesterol. Human genome encodes three alleles of ApoE: E2, E3, and E4. ApoE4 isoform has been well studied in the pathogenesis of Alzheimer’s disease progression and accumulation of beta-amyloid plaques (reviewed in ref.¹⁷¹). ApoE2 isoform has been shown to be associated with increased risk of AMD development and progression¹⁷². An increased lipid deposit within the basal RPE and BrM leading to thickening of BrM is seen in ApoE deleted mice (reviewed in ref.¹⁷³), with increased inflammation, degeneration and exaggerated neovascularization are hallmark features of AMD¹⁷². It has been reported that deletion of VLDLR, a lipoprotein receptor induces neovascularization from superficial retinal vasculature, since lack of VLDLR might result in insufficiency of import of lipoproteins within the RPE and/or retinal cells resulting in cells being deprived of lipids and glucose, driving retinal neovascularization¹⁷⁴. Newly formed blood vessels are often leaky as they are fragile and can cause blindness in late stages of neovascular retinal pathologies. Currently no drugs have been approved for early to intermediate stages of dry AMD, however highly specific inhibitors targeting the C3 and C5 proteins of the complement cascade of the innate immune system have been approved for GA, a late stage dry AMD^175–177. Inhibitors of vascular endothelial growth factor (VEGF), a protein important for formation of new blood vessels, are prescribed for neovascular AMD that prevents further damage to the macula and vision loss¹⁶⁶. However, VEGF inhibitors cannot reverse the damage that has already occurred in the macula, hence an early diagnosis is key to treatment and improving vision. Studies have also linked dietary intake of omega-3 PUFA, an agonist of PPARα with reduced ocular angiogenesis, thus demonstrating protective role of PPARα against neovascular AMD^178,179. Moreover, fenofibrate augmented the overall protective effect of omega-3 PUFA by inhibiting cytochrome P450 epoxygenase (CYP)2 C, thus reducing production of pro-angiogenic metabolites from omega-3 PUFA, thereby inhibiting choroidal neovascularization¹⁸⁰.

Therapeutic approaches to mitigate dyslipidemia

Pharmacological approach

Improving retinal lipid metabolism is being extensively researched to prevent and treat maladies associated with dyslipidemia of retinal cells. Neovascularization is a consequence to overcome growing nutritional demand of retinal cells to fulfil metabolic needs, hence targeting hormonal, transcription factor regulation, lipid metabolism genes, and dietary intervention may protect retinal function. Moreover, targeting dyslipidemia induced inflammatory responses may also prove beneficial. Anti-VEGF drugs are primarily prescribed to treat pathological blood vessel growth in AMD, however it might also affect normal neovascular function in blood and neuronal tissues¹⁸¹. Systemic TAG lowering drugs such as fenofibrate, a PPARα agonist dramatically increases fatty acid ß-oxidation, improves mitochondrial function and energy expenditure, and improved insulin sensitivity. However, decreased levels of PPARα has been implicated in retinal degeneration; thus, fenofibrate prescription prevented DR. In two large scale clinical trials, FIELD, and ACCORD Eye study, fenofibrates were found to significantly benefit DR patients and reduce DR progression by ~40%^157,182. Fenofibrate also improved symptoms of neovascularization, reduced retinal vascular leakage, and downregulated VEGF production in diabetic mice model¹⁸³. Moreover, fenofibrate increases levels of fibroblast growth factor 21 (FGF21), a hormone produced in the liver through activation of PPARα that results in improved metabolic effects like insulin sensitivity, increased TAG mobilization, enhanced FA oxidation, and improved mitochondrial function in muscles and adipose tissue. Thus, FGF21 is crucial for PPARα agonists to ameliorate symptoms of metabolic disorders and hence act as a vital regulator of lipid and glucose metabolism^184,185. FGF21 also enhances retinal antioxidant levels, reduces proinflammatory cytokines, improves cone cell metabolism, and retinal functioning¹⁸⁶. Moreover, FGF21 stimulates production and secretion of adiponectin (APN), a hormone released by fat cells and is implicated in many retinal metabolic disorders¹⁸⁷. FGF21 together with APN reduces accumulation of ceramides in obese mice, increased levels of which contributes to the development of DR, hence targeting ceramide pathway might ameliorate DR symptoms¹⁸⁸.

Stem cell therapy approach

Stem cell therapy is being developed for treatment of retinal degenerative diseases. It has been shown that human pluripotent stem cells (iPS) can be derived into functional RPE (iPS-RPE) that can take up all-trans-retinol from culture media and convert it into 11-cis-retinal for secretion²⁸. These iPS-RPE cells can be used for intraocular or retinal injection, thereby functionally replacing defective RPE¹⁸⁹. Similarly, either transplanting embryonic or iPS derived 3D-retinal sheets into mice retina having advanced retinal degeneration, showed transplanted tissue developed successfully into outer nuclear layer, and inner and outer photoreceptor segments¹⁸⁹. Therefore, transplant therapy holds promise in the treatment of retinal degenerative diseases. More recently, a small group of non-neovascular AMD patients showed enhanced improvement in vision upon successful transplant of a sheet of RPE cells in the degenerated macula. Interestingly, none of the four patients receiving the implant demonstrated any further loss in vision, with one patient being able to view 17 more alphabet letters compared with prior treatment¹⁹⁰.

Other approaches

Consuming a diet rich in vitamin A, antioxidants like lutein and zeaxanthin, and omega 3-fatty acids, found in fish, fish oil, nuts, and purified DHA/EPA supplements, mitigates the pathological effects of RP progression in adults and shows promise in preserving retinal function^191,192. In DR patients, systemic control of elevated blood glucose and lipid levels, and blood pressure remains an effective strategy to prevent development of DR¹⁹³. Use of lipid-lowering drugs such as statins, an inhibitor of HMG-CoA reductase enzyme to block endogenous cholesterol biosynthesis and drugs that control serum apolipoprotein B (apoB), and LDL levels such as ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexsin type 9 (PSCK9), may serve as an effective strategy for DR management^194,195. Recent study in diabetic patients with dyslipidemia showed reduced risk of AMD upon treatment with medium- and high-intensity statin therapies¹⁹⁶. Patients taking lipid-lowering medication showed reduced likelihood to develop DR complications such as NPDR, PDR or the need for intravitreal injection of anti VEGF inhibitor¹⁹⁷. Use of anti-inflammatory agents like Minocycline, a drug that can cross the BBB is being actively researched as a treatment strategy for DR as it can reach inflammatory sites to mediate its action¹⁹⁸.

Future outlook

Growing evidence supports the notion that dyslipidemia due to genetic or acquired factors impair functioning of retinal cells, including photoreceptors resulting in retinal pathologies. Therapeutic approaches to mitigate dyslipidemia through dietary, pharmacological, and lifestyle modification do result in improved retinal degeneration outcomes improving vision; however, the etiology of ophthalmic diseases needs further elucidation to decipher the underlying molecular mechanisms. Future research should investigate the mechanistic insights into how lipid-lowering drugs exert their protective action on retina to develop combination therapy to address co-morbidities such as diabetes and hypertension. Identification and development of eye based biomarkers apart from serum lipid profile for early diagnosis and risk assessment awaits future investigation. Future studies will identify novel lipid-modulating drugs and techniques for precise ocular drug delivery. Developing novel gene therapy approaches targeting retinal degeneration represents an interesting area of research to be translated into clinical practice. Collectively novel prognostic biomarker and therapeutic leads will pave the way for better treatment strategies of retinal degeneration in future.

Author contributions

A.B. prepared the figures. A.B. and V.C. conceived, supervised, and acquired funding for the project. A.B. and V.C.: Writing—Reviewing and Editing. All authors listed above have made substantial, direct, and intellectual contributions to this work and approved it for publication.

Peer review

Peer review information

Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Christina Karlsson Rosenthal. A peer review file is available.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s42003-026-10025-1.