Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells

Abstract

The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ mice.These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content. Mouse OS were also found to express the cholesterol-esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT1), but not lecithin-cholesterol acyltransferase (LCAT), and to differ from humans in retinal expression of ACAT1. Nevertheless, cholesterol esters were discovered to be abundant in human OS. We suggest a mechanism for cholesterol ester accumulation in the OS and that activity impairment of ACAT1 in humans may underlie the development of subretinal drusenoid deposits, a hallmark of age-related macular degeneration, which is a common blinding disease. We generated Cyp27a1؊/؊ mice, characterized their retina by different imaging modalities, and confirmed that unesterified cholesterol does accumulate in their OS and that there is photoreceptor apoptosis and OS degeneration in this line. Our results provide insights into the retinal response to local hypercholesterolemia and the retinal significance of cholesterol esterification, which could be cell-specific and both beneficial and detrimental for retinal structure and function.

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in Cytochrome P450 46A1–Mediated Cholesterol Removal

“…EC was not detectable in the retina of wild-type mice ( Figure 2), whereas in Cyp46a1 À/À mice, it was mainly localized to the photoreceptors and basal membrane of the RPE (Figure 2). Compared with the Cyp27a1 À/À Cyp46a1 À/À retina, 43 there was an additional accumulation of EC in the inner segments of Cyp46a1 À/À mice. Conversely, the inner Cyp46a1 À/À retina had only a faint filipin fluorescence for EC.…”

“…Furthermore, diffuse margins of retinal capillaries during intermediate and late FA stages were indicative of a marked increase in vascular permeability. All of the observed abnormalities were present in the Cyp27a1 À/À Cyp46a1 À/À retina, 43 but in Cyp46a1 À/À mice, these abnormalities were less prominent than in the double-knockout animals.…”

“…Cyp27a1 À/À Cyp46a1 À/À mice, which at the same age had sex-specific amplitude reductions in both scotopic and photopic ERGs. 43 Retinal Vasculature in Cyp46a1 À/À Mice Figure 4A). Initial assessments were conducted on 6-weekeold mice, and no vascular abnormalities were detected (data not shown).…”

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

“…Furthermore, it uses HDL-mediated reverse cholesterol transport and metabolism of cholesterol to more soluble oxysterols for its elimination (49,50). The excess cholesterol may remain in the retina and undergo oxidation because of exposure to light and endogenous free radicals (51,52). Given the fact that LXRs, key regulators of cholesterol homeostasis, are expressed in retina and RPE and oxysterols act as endogenous ligands for LXRs, it is plausible that LXRs may be one of the principal regulators of lipid metabolism and transport in the eye.…”

The Interplay between Retinal Pathways of Cholesterol Output and Its Effects on Mouse Retina

“…Cholesterol esters form lipid droplets, cellular organelles, which provide a unique separation of the aqueous and organic phases of the cell [21]. Cholesterol esters are found in the photoreceptors outer segments, drusen, and Bruch's membrane [2,3,22].Biomolecules 2019, 9, x 2 of 22 decreased risk of progression of non-advanced AMD in specific patient populations [12,13]. Moreover, evidence was obtained that intensive statin therapy may even remove drusen in early stages of AMD [13].…”