Cholesterol and cataracts

Cenedella, Richard J.

doi:10.1016/s0039-6257(96)82007-8

Cited by 112 publications

(98 citation statements)

References 125 publications

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“…sterol to phospholipid as high as 3:1, 22 resulting in cholesterol tail-to-tail bilayer structures similar to those observed in atherosclerotic vascular cell membranes and macrophage foam cells. 23,24 Certain drugs that inhibit cholesterol biosynthesis have been shown to induce cataract development in animal models as a result of reducing essential levels of lens membrane cholesterol.…”

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confidence: 57%

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Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

2004

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Abstract-Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function.(1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.

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confidence: 57%

“…The only mammalian cell type that contains cholesterol microdomains under physiological conditions is the fiber cell of the human ocular lens. 22,23 The plasma membrane of the fiber cell contains molar ratios of Figure 1. Schematic illustration of vessel wall and endothelial cell membrane changes during hyperlipidemia.…”

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confidence: 99%

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

2004

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“…Significant oxidation of cholesterol and\or disturbance of cholesterol homeostasis may well result in cell injury compatible, at least partly, with the damage associated with cataract formation. The presence of cholesterol oxides in human cataracts has not been reported before, nor have the structural and functional implications of the accumulation of such oxides been examined in the lens (Cenedella, 1996).…”

Section: Introductionmentioning

confidence: 96%

Cholesterol Oxides Accumulate in Human Cataracts

Girão

Moța²,

Ramalho³

et al. 1998

Experimental Eye Research

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Human lens membranes contain the highest cholesterol content of any known biological membrane. Although cholesterol is prone to oxidation, the presence of its oxidation products in human cataract has not been shown before. This study was designed to investigate the presence of cholesterol oxides in human cataractous lenses. Human clear lenses (n l 48) were obtained from Coimbra University Hospital Eye Bank. Human cataracts (n l 54) were obtained by routine extracapsular surgery. Cholesterol oxides were isolated by solid-phase extraction on a C ") cartridge and quantified as TMS-ether derivatives by gas chromatography. The extraction procedure allows for an efficient recovery of the major cholesterol oxides, while retaining virtually all cholesterol. Exposure of membranes isolated from transparent human lenses to the free radical generator 2,2h-Azobis(2-amidinopropane) dihydrochloride (AAPH) produced 7α-hydroxycholesterol (6 %), 7β-hydroxycholesterol (19 %), 5α,6α-epoxycholestanol (1 %) and 7-ketocholesterol (74 %) as major oxidation products. Cataractous lenses contained quantifiable amounts of 7β-hydroxycholesterol (7n3p0n74 mmol mol −" cholesterol), 7-ketocholesterol (4n2p0n32 mmol mol −" cholesterol), 5α,6α-epoxycholestanol (0n9p0n16 mmol mol −" cholesterol), 20α-hydroxycholesterol (0n6p0n13 mmol mol −" cholesterol) and 25-hydroxycholesterol (0n1p0n02 mmol mol −" cholesterol), whereas clear lenses contained no detectable amounts of cholesterol oxides. We have shown, for the first time, that oxysterols accumulate in human cataracts. Although the total amount of oxidized cholesterol in cataracts is not likely to be high it may account for much of the membrane damage associated with cataract formation.

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“…However, with the exception of a single case report on the histopathology of the retina of a 1-month-old infant with SLOS (Kretzer et al, 1981), there are no published accounts of the morphological or ultrastructural features of the retina in SLOS, particularly in older patients with more advanced disease. Additional ophthalmic features associated with SLOS, such as cataracts, optic neuropathy, and blepheroptosis, have been reported (Atchaneeyasakul et al, 1998;Cenedella, 1996;Kretzer et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Vaughan

Peachey

Richards

et al. 2006

Experimental Eye Research

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Potentiation of retinal degeneration by intense light exposure, and its amelioration by an antioxidant, were studied in a rat model of Smith-Lemli-Opitz syndrome (SLOS), in comparison with normal (control) Sprague-Dawley rats. The SLOS model is created by treating rats with AY9944, a selective inhibitor of cholesterol synthesis at the level of 3β-hydroxysterol-Δ 7 -reductase. A subset of rats was treated with dimethylthiourea (DMTU), a synthetic antioxidant, 24 and 1 hr prior to light exposure. Half of the animals (±DMTU) were exposed to intense, constant, green light (24 hr, 1700 lx, 490-580 nm), while the others were maintained in darkness. Subsequently all animals were returned to dim cyclic light (20-40 lx, 12 hr light-12 hr dark) for 2 weeks, after which electroretinograms were recorded. One eye from each rat was taken for histological and quantitative morphometric analyses; sterol analysis was performed on retinas from contralateral eyes. HPLC analysis confirmed the accumulation of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats; cholesterol represented >99% of the sterol in control retinas. Histology of retinas from unexposed, AY9944-treated rats (6-week-old) was normal. In contrast, age-matched, light-exposed rats exhibited massive photoreceptor cell loss in both the superior and inferior hemispheres, and concomitant rod and cone dysfunction. The severity and geographic extent of the damage was far greater than that observed in normal albino rats exposed to the same conditions. DMTU pre-treatment largely prevented these degenerative changes. These findings indicate that the AY9944-induced rat SLOS model is hypersensitive to intense light-induced retinal damage, relative to normal rats. DMTU protection against light-induced damage implicates free radical-based oxidation in the retinal degeneration process. Furthermore, the use of green light (corresponding to the absorption maxima of rhodopsin) implicates rhodopsin in the initiation of the pathobiological mechanism. We propose that generation of cytotoxic oxysterols (by-products of 7DHC oxidation) is an integral part of retinal cell death in the SLOS rat model, which is exacerbated by intense light. Furthermore, the results predict lightdependent potentiation of retinal degeneration in SLOS patients, and the possible ameliorative effects of antioxidant therapy.

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Cholesterol and cataracts

Cited by 112 publications

References 125 publications

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

Cholesterol Oxides Accumulate in Human Cataracts

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

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