Cholesterol in the retina: The best is yet to come

Pikuleva, Irina A.; Curcio, Christine A.

doi:10.1016/j.preteyeres.2014.03.002

Cited by 224 publications

(238 citation statements)

References 303 publications

(466 reference statements)

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“…The strong correlation between dietary carbohydrate and lipids within the context of AMDf emphasizes their metabolic connection. C40:6 PC, C22:6 LPE, and C22:6 CE are of particular interest, because soft drusen, an established clinical indication of AMD in humans, contain many such lipids, and variants in cholesterol-related genes are risk factors for AMD (3,52). Our data also point to downstream lipid peroxidation-related products, specifically CEP and 4-HNE, in the etiology of AMDf (37,38).…”

Section: Discussionmentioning

confidence: 67%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

182

192

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Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

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Section: Discussionmentioning

confidence: 67%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

182

192

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“…1B , purple and blue solid and dashed lines). When fed regular rodent chow, 2 H cholesterol enrichment was 20 ± 2% and 9 ± 1% in the retina and brain, respectively, at 2 weeks postinjection with 2 H 2 O. When fed the cholesterolcontaining diet, 2 H cholesterol enrichment was 17 ± 3% in the retina and 11 ± 2% in the brain, statistically insignifi cant changes relative to enrichment measured in animals fed and processed as described ( 13 ).…”

Section: Total Tissue Cholesterol Inputmentioning

confidence: 80%

“…Compensatory reduction of hepatic cholesterol biosynthesis is a reason why mice are resistant to atherosclerosis when challenged with a high-cholesterol diet ( 22 ). 2 H cholesterol enrichments in the retina and brain were lower than those in the liver and serum and showed essentially no response to cholesterol-containing chow ( Fig. 1B , purple and blue solid and dashed lines).…”

Section: Total Tissue Cholesterol Inputmentioning

confidence: 99%

Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Lin

Mast

Bederman

et al. 2016

Journal of Lipid Research

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Cholesterol is a ubiquitous lipid present in the retina ( 1 ), a light-sensitive tissue in the back of the eye that mediates the transmission of the visual signal to the brain. Cholesterol maintenance in the retina is still poorly understood but needs to be studied to delineate the link between retinal cholesterol and age-related macular degeneration (AMD) ( 2 ), a blinding disease affecting the elderly of the industrialized world ( 3 ).The retina maintains cholesterol homeostasis by balancing cholesterol input and output ( 4 ). There are two known pathways of retinal cholesterol input: local cholesterol biosynthesis and tissue uptake of systemic cholesterol (i.e., cholesterol-containing lipoprotein particles from the systemic circulation) ( 5-9 ). The relative contributions, and thus signifi cances, of these pathways to the retinal cholesterol pool are unknown, ultimately impeding the prioritization of research directions in studies of retinal cholesterol ( 2 ).In the present work, we capitalized on the methodological approach developed in our previous investigation of cholesterol input to the brain of mice with disrupted blood-brain barrier ( 10 ). This approach is based on the measurement of the rate of total tissue cholesterol input by administering deuterated water to mice. The rate of tissue uptake of systemic cholesterol is then determined in a separate experiment by feeding mice 2 H-labeled cholesterol. The difference between the two rates can be calculated and represents the rate of tissue cholesterol biosynthesis. We applied our approach to the quantifi cation of cholesterol input to mouse retina and, for comparison, characterized cholesterol input to normal mouse brain, which is also a part of the central nervous system. Both the retina and brain contain neurons and glial cells and are separated from the systemic circulation by the blood-retinal Abstract The retina, a thin tissue in the back of the eye, has two apparent sources of cholesterol: in situ biosynthesis and cholesterol available from the systemic circulation. The quantitative contributions of these two cholesterol sources to the retinal cholesterol pool are unknown and have been determined in the present work. A new methodology was used. Mice were given separately deuterium-labeled drinking water and chow containing 0.3% deuterium-labeled cholesterol. In the retina, the rate of total cholesterol input was 21 g of cholesterol/g retina • day , of which 15 g of cholesterol/g retina • day was provided by local biosynthesis and 6 g of cholesterol/g retina • day was uptaken from the systemic circulation. Thus, local cholesterol biosynthesis accounts for the majority (72%) of retinal cholesterol input. We also quantifi ed cholesterol input to mouse brain, the organ sharing important similarities with the retina. The rate of total cerebral cholesterol input was 121 g of cholesterol/g brain • day with local biosynthesis providing 97% of total cholesterol input. Our work addresses a long-standing question in eye research and adds new knowledge to the...

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“…In addition, the role of alterations in cholesterol homeostasis in drusen development is becoming a subject of increasing research with likely important implications for AMD pathogenesis (Pikuleva and Curcio, 2014).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

Khan

Mahroo

Khan

et al. 2016

Progress in Retinal and Eye Research

166

159

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Drusen are discussed frequently in the context of their association with age-related macular degeneration (AMD). Some types may, however, be regarded as a normal consequence of ageing; others may be observed in young age groups. They also occur in a number of inherited disorders and some systemic conditions. Whilst drusen are classically located external (sclerad) to the retinal pigment epithelium, accumulations of material internal (vitread to) this layer can display a drusen-like appearance, having been variously termed pseudodrusen or subretinal drusenoid deposits. This review first briefly presents an overview of drusen biogenesis and subclinical deposit. The (frequently overlapping) subtypes of clinically detectable deposit, seen usually in the context of ageing or AMD, are then described in more detail, together with appearance on imaging modalities: these include hard and soft drusen, cuticular drusen, reticular pseudodrusen and "ghost drusen". Eye disorders other than AMD which may exhibit drusen or drusen-like features are subsequently discussed: these include monogenic conditions as well as conditions with undefined inheritance, the latter including some types of early onset drusen such as large colloid drusen. A number of systemic conditions in which drusen-like deposits may be seen are also considered. Throughout this review, high resolution images are presented for most of the conditions discussed, particularly the rarer ones, providing a useful reference library for images of the range of conditions associated with drusen-like appearances. In the final section, some common themes are highlighted, as well as a brief discussion of some future avenues for research.

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Cholesterol in the retina: The best is yet to come

Cited by 224 publications

References 303 publications

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

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