Chemistry and metabolism of lipids in the vertebrate retina

Bacterial endophthalmitis is a blinding infectious disease typically acquired during ocular surgery. We previously reported significant alterations in retinal metabolism during Staphylococcus (S) aureus endophthalmitis. However, the changes in retinal lipid composition during endophthalmitis are unknown. Here, using a mouse model of S. aureus endophthalmitis and an untargeted lipidomic approach, we comprehensively analyzed temporal alterations in total lipids and oxylipin in retina. Our data showed a time-dependent increase in the levels of lipid classes, sphingolipids, glycerolipids, sterols, and non-esterified fatty acids, whereas levels of phospholipids decreased. Among lipid subclasses, phosphatidylcholine decreased over time. The oxylipin analysis revealed increased prostaglandin-E2, hydroxyeicosatetraenoic acids, docosahexaenoic acid, eicosapentaenoic acid, and α-linolenic acid. In-vitro studies using mouse bone marrow-derived macrophages showed increased lipid droplets and lipid-peroxide formation in response to S. aureus infection. Collectively, these findings suggest that S. aureus-infection alters the retinal lipid profile, which may contribute to the pathogenesis of bacterial endophthalmitis.

Preclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized evidence for the effects of omega-3 FAs on DR outcomes.

A substudy of the A Study of Cardiovascular Events iN Diabetes (ASCEND) double-blind, randomized, placebo-controlled trial of 1 g omega-3 fatty acids (containing 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15 480 UK adults at least 40 years of age, with diabetes.

Fifteen thousand four hundred eighty adults at least 40 years of age from the United Kingdom with diabetes from the ASCEND cohort.

Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review. Log-rank and stratified log-rank methods were used for intention-to-treat analyses of time until the main outcomes of interest.

The primary efficacy endpoint was time to the first postrandomization recording of referable disease, a composite of referable retinopathy (R₂ or R_3a/s) or referable maculopathy (M₁) based on the grading criteria defined by the United Kingdom National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy.

Linkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 participants (14.8%) had a referable disease event in the omega-3 FAs group, compared with 513 participants (13.9%) in the placebo group (rate ratio, 1.07; 95% confidence interval, 0.95–1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes.

Representing the largest prospective test of its kind to date, these data exclude any clinically meaningful benefits of 1 g daily omega-3 FAs on DR.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Diabetic retinopathy (DR) is a common complication in diabetic patients. DR is also a neurodegenerative disease. Patients with hyperglycemia, hyperlipidemia, and hypertension are vulnerable to retinopathy development. While the roles of blood glucose and blood pressure in the development of retinopathy have been extensively studied, the relationship between body fat and DR pathogenesis and the impact of lipid-reducing drugs on DR has just emerged as a research hotspot in DR study. We aim to visualize the contributions and cooperation of reporters, organizations, and nations, in addition to the research hotspots and trends in DR-related lipid research from 1993 to 2023, by bibliometric analysis.

We extracted all publications about DR-related lipid research from 1993 to 2023 from the Web of Science Core Collection, and bibliometric features were studied using VOSviewer and the CiteSpace program.

1402 documents were retrieved. The number of studies has risen consistently for three decades, from an average of 16.8/year in the 1990s to 28.8/year in the 2000s, 64.5/year in 2010s, and reached 112/year in 2020–2022, confirming they are hot research topic in the field. These reports were from 93 nations/regions, with the USA, China, Japan, Australia, and England taking the leading positions. Diabetes Research and Clinical Practice was the journal that published the most studies, and Diabetes Care was the most quoted. We identified 6979 authors, with Wong TY having the most papers and being the most commonly co-cited. The most popular keyword, according to our research, is diabetic retinopathy. Oxidative stress, diabetic macular edema (DME), lipid peroxidation, and other topics have often been investigated.

DR-related lipid research is conducted mainly in North America, Asia, Oceania, and Europe. Much study has centered on the relationship between lipid-lowering therapy and DR pathogenesis. These studies strongly support using lipid-reducing medications (fenofibrate, statins, and omega-3 PUFAs), combined with hyperglycemia and hypertension therapy, to prevent and treat DR. However, the impact of fenofibrate or statin on retinopathy is not correlated with their action on blood lipid profiles. Thus, more randomized clinical trials with primary endpoints related to DR in T1D or T2D are merited. In addition, the lipid biomarker for DR (lipid aldehydes, ALEs, and cholesterol crystals), the action of lipid-reducing medicines on retinopathy, the mechanism of lipid-lowering medications preventing or curing DR, and ocular delivery of lipid-lowering drugs to diabetic patients are predicted as the research focus in the future in the DR-related lipid research field.

Docosahexaenoic acid (DHA; 22:6) plays a key role in vision and is the precursor for very-long-chain polyunsaturated fatty acids (VLC-PUFAs). The release of 32- and 34-carbon VLC-PUFAs and DHA from sn-1 and sn-2 of phosphatidylcholine (PC) leads to the synthesis of cell-survival mediators, the elovanoids (ELVs) and neuroprotectin D1 (NPD1), respectively. Macula and periphery from age-related macular degeneration (AMD) donor retinas were assessed for the availability of DHA-related lipids by LC-MS/MS-based lipidomic analysis and MALDI-molecular imaging. We found reduced retina DHA and VLC-PUFA pathways to synthesize omega-3 ELVs from precursors that likely resulted in altered disks and photoreceptor loss. Additionally, we compared omega-3 (n-3) fatty acid with DHA (22:6) and omega-6 (n-6) fatty acid with arachidonic acid (AA; 20:4) pathways. n-3 PC(22:6/22:6, 44:12) and n-6 PC(20:4/20:4, 40:8) showed differences among male/female, macula/periphery, and normal/AMD retinas. Periphery of AMD retina males increased 44:12 abundance, while normal females increased 40:8 (all macula had an upward 40:8 tendency). We also showed that female AMD switched from n-3 to n-6 fatty acids; most changes in AMD occurred in the periphery of female AMD retinas. DHA and VLC-PUFA release from PCs leads to conversion in pro-survival NPD1 and ELVs. The loss of the neuroprotective precursors of ELVs in the retina periphery from AMD facilitates uncompensated stress and cell loss. In AMD, the female retina loses peripheral rods VLC-PUFAs to about 33% less than in males limiting ELV formation and its protective bioactivity.

Stargardt maculopathy, caused predominantly by mutations in the ABCA4 gene, is characterized by an accumulation of non-degradable visual pigment derivative, lipofuscin, in the retinal pigment epithelium (RPE) - resulting in RPE atrophy. RPE is a monolayer tissue located adjacent to retinal photoreceptors and regulates their health and functioning; RPE atrophy triggers photoreceptor cell death and vision loss in Stargardt patients. Previously, ABCA4 mutations in photoreceptors were thought to be the major contributor to lipid homeostasis defects in the eye. Recently, we demonstrated that ABCA4 loss of function in the RPE leads to cell-autonomous lipid homeostasis defects. Our work underscores that an incomplete understanding of lipid metabolism and lipid-mediated signaling in the retina and RPE are potential causes for lacking treatments for this disease. Here we report altered lipidomic in mouse and human Stargardt models. This work provides the basis for therapeutics that aim to restore lipid homeostasis in the retina and the RPE.

La rétine est un tissu neurosensoriel particulièrement riche en lipides, et plus particulièrement en acides gras polyinsaturés à longue chaîne de la famille n-3 (AGPI-LC n-3), comme l’acide docosahexaénoïque (DHA). En plus de jouer un rôle prépondérant dans la genèse du signal visuel appelée également « transduction visuelle », ces derniers y exercent des rôles fonctionnels essentiels. En particulier, les AGPI-LC n-3 comme le DHA sont connus pour influencer l’expression génique et ainsi certains mécanismes cellulaires et moléculaires comme l’angiogenèse. Ce mécanisme représente un évènement physiopathologique caractéristique des formes avancées de la dégénérescence maculaire liée à l’âge (DMLA), première cause de malvoyance dans les pays industrialisés. Par ailleurs, des données obtenues chez l’homme ou chez l’animal montrent l’importance de considérer également les AGPI-LC de la série n-6, puisque ces derniers peuvent avoir des effets antagonistes.

The retina is a neurosensory tissue that is characterized by its high contain in lipids and particularly in long-chain polyunsaturated fatty acids from the n-3 series (n-3 LC-PUFA) such as docosahexaenoic acid (DHA). In addition to facilitating visual transduction — the process by which light is converted into electrical signals — lipids play also functional roles that are crucial for cell and tissue homeostasis. In particular, n-3 LC-PUFAs such as DHA are known to influence gene expression thus impacting a number of cellular and molecular mechanisms such as pathological angiogenesis. This mechanism is involved in the pathogenesis of advanced forms of age-related macular degeneration (AMD), the leading cause of vision loss in western countries. On the other hand, data from human and animal studies underline the importance of considering also n-6 LC-PUFAs as they display antagonist effects.