Targeting Lipid Metabolism for the Treatment of Age-Related Macular Degeneration: Insights from Preclinical Mouse Models

Landowski, Michael; Rickman, Catherine Bowes

doi:10.1089/jop.2021.0067

Cited by 27 publications

(31 citation statements)

References 316 publications

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“…Dysregulation in lipid/cholesterol homeostasis is linked to age-related diseases and loss of RPE function [ 55 , 56 , 57 ]. Several features observed in the LC3b −/− RPE, such as reduced phagocytosis, lipid deposits, recruitment of immune cells, and complement pathway activation are reminiscent of AMD-like pathophysiology [ 28 , 58 , 59 , 60 ].…”

Section: Resultsmentioning

confidence: 99%

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Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Dhingra

Tobias

Philp

et al. 2023

IJMS

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LC3b (Map1lc3b) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes, such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells, utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis, and neuroprotection. In a mouse model of retinal lipid steatosis-mice lacking LC3b (LC3b−/−), we observed increased lipid deposition, metabolic dysregulation, and enhanced inflammation. Herein, we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b−/− mice revealed 1533 DEGs, with ~73% upregulated and 27% downregulated. Enriched gene ontology (GO) terms included inflammatory response (upregulated DEGs), fatty acid metabolism, and vascular transport (downregulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with a potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.

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Section: Resultsmentioning

confidence: 99%

“…What role this gene editing activity plays in RPE-specific β-lipoproteins assembly is unknown. Further studies are necessary to understand how cholesterol biosynthesis and packaging in lipoproteins is influenced by LAP with an emphasis on therapeutics designed to restore lipid homeostasis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Dhingra

Tobias

Philp

et al. 2023

IJMS

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“…We have previously demonstrated that ANGPTL4 can promote both angiogenesis ( 32 , 42 ) and vascular permeability ( 34 , 41 , 59 ), the latter through promotion of the Rho/ROCK pathway ( 41 ). In addition to regulating angiogiogenesis, ANGPTL4 has also been reported to regulate lipid metabolism ( 60 ) and inflammation ( 61 ), both of which have also been implicated in the pathogenesis of AMD ( 62 , 63 ). Additional studies will be necessary to determine the mechanisms by which ANGPTL4 contributes to the development of CNV in patients with nvAMD.…”

Section: Discussionmentioning

confidence: 99%

ANGPTL4 influences the therapeutic response of patients with neovascular age-related macular degeneration by promoting choroidal neovascularization

Yu¹,

Dinabandhu²,

Sanchez³

et al. 2022

JCI Insight

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Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single angiogenic mediator, vascular endothelial growth factor (VEGF). Here, we report that aqueous fluid levels of a second vasoactive mediator, angiopoietin-like 4 (ANGPTL4), can help predict the response of patients with nvAMD to anti-VEGF therapies. ANGPTL4 expression was higher in patients who required monthly treatment with anti-VEGF therapies compared with patients who could be effectively treated with less-frequent injections. We further demonstrate that ANGPTL4 acts synergistically with VEGF to promote the growth and leakage of choroidal neovascular (CNV) lesions in mice. Targeting ANGPTL4 expression was as effective as targeting VEGF expression for treating CNV in mice, while simultaneously targeting both was more effective than targeting either factor alone. To help translate these findings to patients, we used a soluble receptor that binds to both VEGF and ANGPTL4 and effectively inhibited the development of CNV lesions in mice. Our findings provide an assay that can help predict the response of patients with nvAMD to anti-VEGF monotherapy and suggest that therapies targeting both ANGPTL4 and VEGF will be a more effective approach for the treatment of this blinding disease.

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“…Lipid metabolism is regulated by apolipoproteins, structural proteins essential for the metabolism of triglycerides and cholesterol. Lipoproteins found in the posterior ocular segment are part of a distinct class of lipoproteins similar to very low-density lipoproteins (VLDL) concerning size, but they are structurally similar to LDL, as they are rich in esterified cholesterol [5,18]. Apolipoprotein E (ApoE) was identified as a major drusen component.…”

Section: Dyslipidemia and Its Effects In The Eyementioning

confidence: 99%

“…In lipoproteins, ApoE functions to facilitate their cellular uptake, binding to extracellular matrices, thus allowing efficient delivery and removal of lipids from cells. Besides ApoE, other lipid components were found in drusen composition, such as esterified cholesterol, unesterified cholesterol, phosphatidylcholine, triglycerides, sphingomyelin, fatty acids, and other apolipoproteins [8,18]. The oxidation of these lipids and proteins can contribute to a pro-inflammatory environment, promoting the development of AMD.…”

Section: Dyslipidemia and Its Effects In The Eyementioning

confidence: 99%

Precision Medicines for Retinal Lipid Metabolism-Related Pathologies

Ana

Gliszczyńska

García

et al. 2023

JPM

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Oxidation of lipids and lipoproteins contributes to inflammation processes that promote the development of eye diseases. This is a consequence of metabolism dysregulation; for instance, that of the dysfunctional peroxisomal lipid metabolism. Dysfunction of lipid peroxidation is a critical factor in oxidative stress that causes ROS-induced cell damage. Targeting the lipid metabolism to treat ocular diseases is an interesting and effective approach that is now being considered. Indeed, among ocular structures, retina is a fundamental tissue that shows high metabolism. Lipids and glucose are fuel substrates for photoreceptor mitochondria; therefore, retina is rich in lipids, especially phospholipids and cholesterol. The imbalance in cholesterol homeostasis and lipid accumulation in the human Bruch’s membrane are processes related to ocular diseases, such as AMD. In fact, preclinical tests are being performed in mice models with AMD, making this area a promising field. Nanotechnology, on the other hand, offers the opportunity to develop site-specific drug delivery systems to ocular tissues for the treatment of eye diseases. Specially, biodegradable nanoparticles constitute an interesting approach to treating metabolic eye-related pathologies. Among several drug delivery systems, lipid nanoparticles show attractive properties, e.g., no toxicological risk, easy scale-up and increased bioavailability of the loaded active compounds. This review analyses the mechanisms involved in ocular dyslipidemia, as well as their ocular manifestations. Moreover, active compounds as well as drug delivery systems which aim to target retinal lipid metabolism-related diseases are thoroughly discussed.

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Targeting Lipid Metabolism for the Treatment of Age-Related Macular Degeneration: Insights from Preclinical Mouse Models

Cited by 27 publications

References 316 publications

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

ANGPTL4 influences the therapeutic response of patients with neovascular age-related macular degeneration by promoting choroidal neovascularization

Precision Medicines for Retinal Lipid Metabolism-Related Pathologies

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