Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Abstract

Journal of Lipid Research Volume 51, 20102847 their actions affect the retina and the retinal pigment epithelium (RPE) ( 8-10 ). One particular oxysterol, 7-ketocholesterol (7KCh), has been found more abundantly than other oxysterols in the retina ( 9, 10 ). This oxysterol is known to have potent pharmacological properties that lead to infl ammation and cell death in a variety of cell types ( 1-10 ). This review will focus on what is known about this molecule and the potential implications of its presence in the retina. The retina is a light-capturing tissue that contains at least 5 cell classes and more than 50 different cell types, each performing unique functions that ultimately provide the visual centers in the brain the information to achieve image formation and visual perception. The retina faces a unique photooxidative environment that generates challenges not encountered by other neurological tissues or organs. Phototransduction requires the retina to have a high metabolic rate ( 11 ) and multiple and complex membrane structures ( 12 ). The photoreceptor outer segments are enriched in the highly photosensitive docosahexaenoic acid and other Abstract This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinfl ammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor B and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of effl ux mechanism may be active. The chronic mode of formation and the potent infl ammatory properties of 7KCh indicate it may be an "age-related" risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration. -Rodríguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res . 2010. 51: 2847-2862. Supplementary key words 7-ketocholesterol • cytokines • oxysterolsIn the past year, numerous reviews have been published that extensively discuss the multiple functions of oxysterols and their complex relationships to diseases ( 1-7 ). However, the formation and function of oxysterols in the retina has not been well studied. Emerging studies are...

Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant CYP27A1 and retinal pigment epithelial cells

“…By using in vitro assays, we demonstrated for the fi rst time that purifi ed recombinant CYP27A1 binds and metabo- compared with the 27COOH/cholesterol ratio may refl ect either more effi cient metabolism of 7KCh relative to cholesterol or less effi cient elimination of 7KCh-27OH relative to 27COOH. The former would be in agreement with the results of our in vitro studies evaluating cholesterol and 7KCh as the substrates for CYP27A1, as well with prior investigations by others showing cytotoxic, pro-infl ammatory, and apoptotic effects of 7KCh on the RPE-derived cells ( 4,15,44 ). 27-Hydroxylation seems to reduce toxicity of 7KCh as demonstrated by survival of the RPE cells treated with 7KCh-27OH at concentrations and time in which 7KCh essentially killed the entire culture ( 15 ).…”

“…In any case, the range of the 7KCh concentrations in bovine neural retina and RPE (0.07-0.36 pmol/nmol cholesterol) was more comparable to the 7KCh levels in hamster brain ( ‫ف‬ 0.05 pmol/nmol cholesterol) ( 38 ) with higher concentrations in the neural retina possibly refl ecting its unique oxidative environment (reviewed in Ref. 4 ).…”

“…Evidence was obtained indicating that iron is likely involved in generation of 7KCh in the neural retina ( 9 ). The source of iron was not determined, but ferritin and/or cytochrome c are suspected ( 4 ). The routes of 7KCh elimination from the retina are also under investigation.…”

“…Four pathways are considered: i ) enzymatic oxidation by cholesterol 25-hydroxylase and cytochrome P450 enzymes 27A1 and 46A1 (CYP27A1 and CYP46A1); ii ) reduction by 11 ␤ -hydroxysteroid dehydrogenase type 1; iii ) effl ux involving transporters such as ABCA1 and ABCG5; and iv ) sulfonation by sulfotransferases (reviewed in Ref. 4 ). Of these four possible pathways, we favor enzymatic oxidation of 7KCh by CYP27A1, a ubiquitous sterol 27-hydroxylase with relatively broad substrate specifi city and multiple physiological roles.…”

Structural characterization of human cholesterol 7α-hydroxylase

“…Aliquots (0.5 ml) were taken from the incubation mixture at selected time intervals. Steroids were extracted with 5 ml pathways in the retina, 7KCh might be a pathogenetic factor in age-related macular degeneration ( 9 ). The major routes for 7KCh metabolism include a ) conversion into less toxic 27-hydroxylated 7KCh by CYP27A1/CYP46A1 ( 10-13 ) and further to more water-soluble metabolites, thus protecting mitochondria from reactive oxygen species; b ) esterifi cation including sulfonation ( 14 ); c ) lipoprotein-mediated elimination ( 15 ); and d ) interconversion to 7 ␤ -hydroxycholesterol by 11 ␤ -hydroxysteroid dehydrogenase type 1 ( 16,17 ).…”