Oxysterols: Influence on plasma membrane rafts microdomains and development of ocular diseases

Oxidation of cholesterol into oxysterols is a major way of elimination of cholesterol from the liver and extrahepatic tissues, including the brain and the retina. Oxysterols are involved in various cellular processes. Numerous links have been established between oxysterols and several disorders such as neurodegenerative pathologies, retinopathies and atherosclerosis. Different components of the lipid layer such as sphingolipids, sterols and proteins participate to membrane fluidity and forme lipid rafts microdomains. Few data are available on the links between lipids rafts and oxysterols. The purpose of this review is to suggest the potential role of lipid rafts microdomains in the developm…

Cholestérol et pathologies oculaires : focus sur le rôle de la cholestérol 24S-hydroxylase (CYP46A1) dans l’homéostasie du cholestérol

Resume La retine est le tissu neurosensoriel de l’œil qui assure la transduction visuelle, c’est-a-dire le codage de l’information lumineuse en influx nerveux. Le terme « retine » regroupe l’association de la retine neurale et de l’epithelium pigmentaire retinien qui repose sur la membrane de Bruch. L’association physique de ces deux partenaires et leurs interactions metaboliques sont des elements indispensables au bon fonctionnement de la retine, a la fois en termes d’apport en nutriments et de maintien de l’homeostasie. Des dereglements de ces equilibres sont associes au vieillissement et a des pathologies comme la degenerescence maculaire liee a l’âge, premiere cause de malvoyance apres …

Cholestérol et pathologies oculaires

Cholesterol metabolism via cyp46a1 in glaucoma

Cholesterol metabolism via cyp46a1 in glaucoma. International society for eye research (ISER) annual meeting

Effects of 24s-hydroxycholesterol on primary glial Müller cells. New insights on Müller cells function and cholesterol homeostasis in the retina

Purpose: Müller cells are macroglial cells in the retina. These cells express various proteins known to undergo glutamate clearance, which dysfunction may be involved in the loss of retinal ganglion cells (RGC) in the course of glaucoma. In neurons and especially in RGC, 24S-hydroxycholesterol (24SOH) is a metabolite produced by conversion of cholesterol by cholesterol 24S-hydroxylase (CYP46A1). This process participates to cholesterol homeostasis by facilitating the removal of cholesterol from neurons. 24SOH might be a signal molecule ensuring the cross-talk between neurons and glia, and putatively between RGC and glia. The aim of our study was to emphasize the response of primary Müller c…

Cholesterol and ocular pathologies: focus on the role of cholesterol-24S-hydroxylase in cholesterol homeostasis

The retina is responsible for coding the light stimulus into a nervous signal that is transferred to the brain via the optic nerve. The retina is formed by the association of the neurosensory retina and the retinal pigment epithelium that is supported by Bruch’s membrane. Both the physical and metabolic associations between these partners are crucial for the functioning of the retina, by means of nutrient intake and removal of the cell and metabolic debris from the retina. Dysequilibrium are involved in the aging processes and pathologies such as age-related macular degeneration, the leading cause of visual loss after the age of 50 years inWestern countries. The retina is composed of severa…

In vivo consequences of cholesterol-24s-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina

Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina. We aimed to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina. Rats received daily intraperitoneal injections of voriconazole (60mg/kg), minocycline (22mg/kg), voriconazole plus minocycline, or vehicle during five consecutive days. The rats were submitted to electroretinography to monitor retinal functionality. Cholesterol and 24S-hydroxycholesterol were measured in plasma, brain and retina by gas chromatography-mass spectrometry. T…

In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina

International audience; Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina. We aimed to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina. Rats received daily intraperitoneal injections of voriconazole (60 mg/kg), minocycline (22 mg/kg), voriconazole plus minocycline, or vehicle during five consecutive days. The rats were submitted to electroretinography to monitor retinal functionality. Cholesterol and 24S-hydroxycholesterol were measured in plasma, brain and retina by gas chromatog…

Cholestérol-24S-hydroxylase (CYP46A1) et homéostasie du cholestérol dans la rétine en conditions physiologiques et pathologiques

Cholesterol is the major sterol found in the retina. In its free form, cholesterol is present in all cell layers of the retina, whereas cholesteryl esters mainly accumulate at the basement of the retinal pigment epithelium. The intrinsic capacity of the retina to synthetize cholesterol appears limited. Some extra-retinal pathways actively participate to cholesterol uptake to the retina. Müller glial cells may contribute to cholesterol supply to retinal neurons, especially for synaptic formation. Cholesterol accumulation or conversely deficiency have deleterious consequences on neuron survival. Maintaining the equilibrium between cholesterol supply and neosynthesis in the one hand and choles…

Early adaptive response of the retina to a pro-diabetogenic diet: Impairment of cone response and gene expression changes in high-fructose fed rats

The lack of plasticity of neurons to respond to dietary changes, such as high fat and high fructose diets, by modulating gene and protein expression has been associated with functional and behavioral impairments that can have detrimental consequences. The inhibition of high fat-induced rewiring of hypothalamic neurons induced obesity. Feeding rodents with high fructose is a recognized and widely used model to trigger obesity and metabolic syndrome. However the adaptive response of the retina to short term feeding with high fructose is poorly documented. We therefore aimed to characterize both the functional and gene expression changes in the neurosensory retina of Brown Norway rats fed duri…

Cholesterol homeostasis and retinal stress in anterior ischemic optic neuropathy

Purpose: Anterior ischemic optic neuropathy (AION) is characterized by acute stress of retinal ganglion cells (RGC). Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in RGC where it may exert neuroprotective properties by preventing from cholesterol accumulation via catalyzing the formation of 24S-hydroxycholesterol. Previous findings hypothesize the housekeeping importance of CYP46A1 in the maintenance of cholesterol in the retina. In order to better understand the role of CYP46A1 in the retina, we aimed to define whether CYP46A1 expression and 24S-hydroxycholesterol levels were modified during RGC stress in AION.Methods: Ninety nine male Sprague Dawley rats were randomized …

Ether-Lipids Are Involved in Retinal Vegf Expression and in Postnatal Hyaloid Vessel Regression

Purpose:Ether-lipids are phospholipids that represent about 13% of retinal lipids and whose exact functions remain unknown. However, the preferential esterification of polyunsaturated fatty acids (PUFAs) at the sn-2 position of ether-lipids and their liberation by an ether-lipid-specific phospholipase A2 suggest their involvement in cell signaling processes. Based on the data showing the persistence of the hyaloid vasculature in ether-lipid-deficient mice (DAPAT-/- mice, Rodemer et al Hum Mol Genet 2003), we further investigated the molecular mechanisms by which ether-lipids may regulate hyaloid vessels regression during post-natal development. Methods:C57BL/6 mice were treated at birth eit…

Acides gras polyinsaturés de la rétine : ont-ils une origine alimentaire ? Lipid Nutri+

National audience; L’objectif du présent article est de faire le point sur l’origine des acides gras polyinsaturés dans la rétine neurale, en se focalisant en particulier sur le DHA. Nous appuierons notre propos en particulier sur nos données récentes obtenues sur des sujets décédés chez qui la rétine neurale et le couple EPR/choriocapillaire ont été prélevés et analysés pour leur contenu en lipides. Le profil en acides gras du tissu adipeux nous a servi de marqueur de consommation. Nous avons ainsi pu rechercher si les teneurs en AGPI de la rétine neurale sont le reflet des habitudes alimentaires des sujets.

Dietary polyunsaturated fatty acids reduce retinal stress induced by an elevation of intraocular pressure in rats.

International audience; N-6 and n-3 polyunsaturated fatty acids (PUFAs) have been shown to prevent tissue release of inflammatory molecules. We have shown that a combination of n-6 and n-3 PUFAs is more efficient than single supplementations on the long-term consequences of intraocular pressure elevation. We hypothesized that such an association is also more effective during early retinal stress by modifying retinal proinflammatory prostaglandin and cytokine productions. Rats were supplemented for 3 months with n-6 PUFAs, n-3 PUFAs, or both n-6 and n-3 PUFAs. After 3 months, a surgical elevation of intraocular pressure was induced. Retinal morphometry and glial cell activation were evaluate…

24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma.

http://www.sciencedirect.com/; International audience; Free cholesterol is the predominant form of cholesterol in the neural retina. The vertebrate neural retina exhibits its own capacity to synthesize cholesterol and meets its demand also by taking it from the circulation. Defects in cholesterol synthesis and trafficking in the neural retina has detrimental consequences on its structure and function, highlighting the crucial importance of maintaining cholesterol homeostasis in the retina. Our purpose was to give a review on the functioning of the retina, the role of cholesterol and cholesterol metabolism therein, with special emphasis on cholesterol-24S-hydroxylase (CYP46A1). Similar to th…

Cholesterol homeostasis and retinal stress in anterior ischemic optic neuropathy

International audience

Steady-state levels of retinal 24S-hydroxycholesterol are maintained by glial cells intervention after elevation of intraocular pressure in the rat

Purpose: Our previous studies suggested that CYP46A1 and 24S-hydroxycholesterol. (24SOH) may be associated with glaucoma. Loss of CYP46A1-expressing retinal. ganglion cells is involved in the activation of glia, and therefore possibly in the. disbalance of cholesterol. In this context, the purpose of our present work was to. emphasize the glial and longitudinal CYP46A1 expression after an interventional. glaucoma-related stress triggered by elevated intraocular pressure (IOP). Methods: Sprague–Dawley rats were submitted to laser photocoagulation of the. trabecular meshwork, limbus and episcleral veins in one eye to induce elevated IOP. Rats were euthanized at days 3, 14, 30 and 60 (n = 10 p…

Preparation of recombinant rotavirus proteins in milk of transgenic non-human mammals

Numéro publication: WO 2005/084427 A1