Cholesterol in the retina: The best is yet to come
Introduction
Cholesterol is often viewed as a deleterious compound, mainly because its excess in systemic circulation is a risk factor for cardiovascular and Alzheimer's diseases (Anonymous, 2002, Solomon et al., 2009, Zambon et al., 2010). Yet cholesterol is involved in many physiological processes and thus a lipid essential for normal human development, growth and physiology.
Studies of cholesterol will be moving to the forefront of vision research because of accumulating data implicating cholesterol homeostasis in the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible vision loss and blindness in the elderly of industrialized world (Pascolini et al., 2004). Evidence linking cholesterol and AMD emerged more than a decade ago when cholesterol has been discovered to accumulate with age in human Bruch's membrane (BrM) (Curcio et al., 2001). Subsequent studies also established that esterified (EC) and unesterified cholesterol (UC) are significant components of the lipid-rich lesions associated with AMD (basal linear deposits, BLinD, and soft drusen) and comprise >40% of hard druse volume (Curcio et al., 2011a). The cholesterol-AMD link was confirmed when variants in the cholesterol-related genes were found to be associated with AMD by genome-wide association studies (GWAS) that suggested that these variants may play important roles in early AMD (Chen et al., 2010, Fritsche et al., 2013, Neale et al., 2010, Yu et al., 2012). As a result of all these developments, the investigation of the impact of cholesterol and lipoproteins for AMD, inflammation and angiogenesis has been included in the 2012 report of the National Eye Institute “Vision Research: Needs, Gaps and Opportunities” (http://www.nei.nih.gov/strategicplanning/), which represents a part of the institute strategic planning.
Hopefully, the delineation of the cholesterol-AMD link will follow a more rapid time course than the cholesterol-cardiovascular disease saga (Steinberg, 2004, Steinberg, 2005a, Steinberg, 2005b, Steinberg, 2006a, Steinberg, 2006b). Indeed, it took more than 70 years for the “lipid hypothesis” of atherosclerosis to become widely accepted after it was first introduced by Anitschkow, 1913 in his classic work on cholesterol-fed rabbits. Even in the middle of 1940's, most physicians considered atherosclerosis as an inevitable disease of aging (Steinberg, 2004). Now we have a good understanding of how cholesterol homeostasis in maintained in a whole body and many organs (Bjorkhem and Meaney, 2004, Brown and Goldstein, 2009, Kalaany and Mangelsdorf, 2006, Norlin and Wikvall, 2007, Russell, 2008), effective and safe cholesterol-lowering drugs, and public awareness of the benefits of a healthy life style and diet. These advances, along with those in cardiovascular surgery, has led to a continued decline (by a total of 43% from 1999 to 2010) in mortality rates for cardiovascular disease (http://www.cdc.gov/nchs/healthy_people/hp2010/hp2010_final_review.htm), an inspiring example for researchers and clinicians combating AMD. The expertise gained in that great public health success is now available to be applied to AMD.
There seems to be increased interest in chorioretinal cholesterol within the last several years as reflected by the thematic review series in the Journal of Lipid Research (Curcio et al., 2010, Fliesler, 2010a, Fliesler and Bretillon, 2010, Rodriguez and Larrayoz, 2010) and review articles on this topic in the specialized eye publications including this journal (Curcio et al., 2009a, Curcio et al., 2011a, Javitt and Javitt, 2009, van Leeuwen et al., 2004). For a detailed overview of cholesterol-related research in the vision field, readers are advised to refer to excellent and comprehensive previous reviews (Albert and Boesze-Battaglia, 2005, Curcio et al., 2010, Curcio et al., 2009a, Curcio et al., 2011a, Fliesler, 2010b, Fliesler and Bretillon, 2010, Fourgeux et al., 2011, Rodriguez and Larrayoz, 2010). The goal of the present paper is to summarize the most recent findings and provide a general view of where we stand in our current knowledge of chorioretinal cholesterol. This view represents the combined expertise of the two investigators, IAP and CAC, with relevant biochemistry and pathology publications. In writing this chapter we wish to recognize and express gratitude for the singular contributions of investigators who pioneered the study of retinal cholesterol and gave us our first glimpses of its localization, regulation, trafficking, toxic by-products, and potential for therapeutic intervention (Boesze-Battaglia et al., 1989, Fliesler and Schroepfer, 1982, Rodriguez and Larrayoz, 2010, Tserentsoodol et al., 2006a).
We begin by providing the background information on cholesterol and outlining how cholesterol homeostasis is maintained in a whole body with particular emphasis on cholesterol-related genes implicated in AMD. Then we will move to the major theme of this paper, chorioretinal cholesterol, and present our data and thoughts on how cholesterol homeostasis is maintained in the neural retina (NR), retinal pigment epithelium (RPE) and BrM, and the cholesterol-AMD link could be realized. We will conclude by pointing to the most important, in our opinion, directions of cholesterol-related research in vision field.
Section snippets
Physico-chemical properties, physiological roles, and distribution in a human body
Cholesterol is a lipid composed of a four-ring system flanked by a hydroxyl group at carbon 3 of the ring A and a branched hydrocarbon side chain at carbon 17 of the ring D (Fig. 1A). The fused ring system is rigid and flat, whereas the side chain is flexible and puckered (Fig. 1B). Most of the molecule is hydrophobic, except the 3β-hydroxyl group, which is hydrophilic, making cholesterol an amphipathic lipid. In addition to polarity, the 3β-hydroxyl renders cholesterol the ability to form
NR, RPE and BrM
The term “retina” is often referred to the structure comprised of the three principally different components: NR, RPE and choroid (Fig. 4), with the latter two constituting the support system of the photoreceptors (PR). It is essential to understand the layers, compartments, and regions affected by AMD, because AMD pathology itself shows precise laminar and topographic predilections. Of major significance are the two physiological universes of the retina: inside the blood-retina barrier and
Drusen, BLinD, and SDD
AMD can be productively considered a multifactorial disease of the PR support system, involving the RPE and BrM. AMD has vascular, metabolic, and inflammatory components, with a secondary neurodegeneration of the PR. Thus AMD is distinguished from the many monogenic diseases affecting primarily photoreceptors. PR degeneration and loss is the basis of visual dysfunction in AMD. These occur in the setting of a thick and stereotypic deposition of extracellular material, interposed between outer
Future directions
We offer a Top Twelve list of current pressing questions about the role of cholesterol in the retina, organized into groups pertinent to biochemistry/nutrition of chorioretinal region, AMD pathobiology, and translational research.
Conclusions
Studies of chorioretinal cholesterol have reached an exciting stage when accumulated knowledge can newly inform pre-clinical/clinical studies. Many open questions remain, so additional human and capital resources will certainly be required. Yet we can take heart in one of medicine's greatest public health successes. A decades-long decline in cardiovascular disease and stroke was propelled by risk factor reduction and drugs precisely targeted to blunt the effects of lipid-rich lesions in vessel
Acknowledgments
This research was supported in part by grants from the National Institutes of Health (EY018383 to IAP and EY06109 to CAC). IAP is a recipient of the Jules and Doris Stein Professorship from the Research to Prevent Blindness.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Christine A Curcio: 50%; Irina A. Pikuleva: 50%.