The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts

Madjedi, Kian; Stuart, Kelsey V.; Chua, Sharon; Luben, Robert; Warwick, Alasdair; Pasquale, Louis R.; Kang, Jae H.; Wiggs, Janey L.; Lentjes, Marleen; Aschard, Hugues; Sattar, Naveed; Foster, Paul J.; Khawaja, Anthony P

doi:10.1016/j.ophtha.2022.04.023

Cited by 21 publications

(20 citation statements)

References 48 publications

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“…32,[89][90][91] Some well-studied lipids contributing to ocular hypertension are the bioactive lysophospholipids (lipid growth factors), 33,[92][93][94][95] and cholesterol. [34][35][36] Yet, the causality has not been completely attributed to increased lipids on IOP elevation. Based on recent epidemiologic studies, there is an association between cholesterol and glaucoma, although the findings have not been if hyperlipidemia is a cause or an effect of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperlipidemia is associated with an increased risk of elevated IOP and glaucoma with poor mechanistic understanding. [34][35][36] Interestingly, cholesterol-lowering statins lower IOP and reduce the incidence of glaucoma. [37][38][39] Mechanistic studies in TM point at statin-mediated disruption of membrane association of Rho GTPase due to inhibition of the isoprenylation of Rho.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Wang,

Soundararajan,

Rabinowitz

et al. 2023

The FASEB Journal

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Trabecular meshwork (TM) cells are contractile and mechanosensitive, and they aid in maintaining intraocular pressure (IOP) homeostasis. Lipids are attributed to modulating TM contractility, with poor mechanistic understanding. In this study using human TM cells, we identify the mechanosensing role of the transcription factors sterol regulatory element binding proteins (SREBPs) involved in lipogenesis. By constitutively activating SREBPs and pharmacologically inactivating SREBPs, we have mechanistically deciphered the attributes of SREBPs in regulating the contractile properties of TM. The pharmacological inhibition of SREBPs by fatostatin and molecular inactivation of SREBPs ex vivo and in vivo, respectively, results in significant IOP lowering. As a proof of concept, fatostatin significantly decreased the SREBPs responsive genes and enzymes involved in lipogenic pathways as well as the levels of the phospholipid, cholesterol, and triglyceride. Further, we show that fatostatin mitigated actin polymerization machinery and stabilization, and decreased ECM synthesis and secretion. We thus postulate that lowering lipogenesis in the TM outflow pathway can hold the key to lowering IOP by modifying the TM biomechanics.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Wang,

Soundararajan,

Rabinowitz

et al. 2023

The FASEB Journal

View full text Add to dashboard Cite

show abstract

“…The current understanding of the correlation between the regulation of lipid levels in the TM outflow pathway with IOP changes is unclear. Lipids levels are known to be varied in aqueous humor from ocular hypertensives (76) (28,77) and can participate in the pathogenesis of elevated IOP -the bioactive lysophospholipids (lipid growth factors) (29,(78)(79)(80)(81), and cholesterol (30)(31)(32). Yet the causality has not been completely attributed to increased lipids on IOP elevation.…”

Section: Discussionmentioning

confidence: 99%

“…This is attributed via modulating the signaling events including altering the TM contractility and tissue stiffness. Hyperlipidemia is associated with an increased risk of elevated IOP and glaucoma with poor mechanistic understanding (30)(31)(32). Interestingly, cholesterol-lowering statins lower IOP and reduce the incidence of glaucoma (33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Wang

Soundararajan

Rabinowitz

et al. 2023

Preprint

View full text Add to dashboard Cite

Trabecular meshwork (TM) cells are highly contractile and mechanosensitive to aid in maintaining intraocular pressure (IOP) homeostasis. Lipids are attributed to modulating the TM contractility with poor mechanistic understanding. In this study using human TM cells, we identify the mechanosensing role of the transcription factors sterol regulatory element binding proteins (SREBPs) involved in lipogenesis. By constitutively activating SREBPs and pharmacologically inactivating SREBPs, we have mechanistically deciphered the attributes of SREBPs in regulating the contractile properties of TM. The pharmacological inhibition of SREBPs by fatostatin and molecular inactivation of SREBPs ex vivo and in vivo respectively results in significant IOP lowering. As a proof of concept, fatostatin significantly decreased the SREBPs responsive genes and enzymes involved in lipogenic pathways as well as the levels of the phospholipid, cholesterol, and triglyceride. Further, we show that fatostatin mitigated actin polymerization machinery and stabilization, and decreased ECM synthesis and secretion. We thus postulate that lowering lipogenesis in the TM outflow pathway can hold key to lowering IOP by modifying the TM biomechanics.

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“…Previous studies, using eye and vision cohorts, have investigated potential risk factors for developing eye diseases, for example lifestyle, systemic diseases and alterations in the vascular system (Chua et al, 2021;Madjedi et al, 2022;Owen et al, 2019;Yip et al, 2014aYip et al, , 2014b. The UK Biobank Eye and Vision sub-cohort is the world's largest prospective eye cohort including a total of 502 665 participants with data collected between January 2006 and October 2010 (Chua et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability (FOREVER)—A cohort study in a Danish high street optician setting: Design and methodology

Gazzard

Kolko

Torp‐Pedersen³

et al. 2023

Acta Ophthalmologica

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PurposeThe purpose of the study was to describe the rationale and design of Project FOREVER (Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability).DesignProject FOREVER will build a comprehensive database of clinical eye and vision data collected from ~280 000 adults at 100 optician stores across Denmark. The FOREVER database (FOREVERdb) includes detailed data from refraction, visual acuity, intraocular pressure, corneal thickness, visual field assessments and retinal fundus images. Linkage to the comprehensive Danish national registries with, that is diagnostic and prescribing data permits investigation of rare associations and risk factors. 30 000 individuals over 50 also provide a saliva sample for later genetic studies and blood pressure measurements. Of these 30 000, 10 000 will also get optical coherence tomography (OCT) nerve and retinal scans. This subpopulation data is reviewed by ophthalmologists for disease detection. All participants will be asked to complete a questionnaire assessing lifestyle, self‐perceived eye health and general health. Enrolment of participants began in April 2022.PerspectiveThe FOREVERdb is a powerful tool to answer a wide range of research questions that can pave the way for better eye health. This database will provide valuable insights for future studies investigating the correlations between eye and general health in a Danish population cohort, enabling research to identify potential risk factors for a range of diseases.

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The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts

Cited by 21 publications

References 48 publications

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability (FOREVER)—A cohort study in a Danish high street optician setting: Design and methodology

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