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      Contribution of Cholesterol and Oxysterols in the Physiopathology of Cataract: Implication for the Development of Pharmacological Treatments

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          Abstract

          The development of cataract is associated with some lipid changes in human lens fibers, especially with increased accumulation and redistribution of cholesterol inside these cells. Some direct and indirect lines of evidence, also suggest an involvement of cholesterol oxide derivatives (also named oxysterols) in the development of cataract. Oxysterol formation can result either from nonenzymatic or enzymatic processes, and some oxysterols can induce a wide range of cytotoxic effects (overproduction of reactive oxygen species (ROS); phospholipidosis) which might contribute to the initiation and progression of cataract. Thus, the conception of molecules capable of regulating cholesterol homeostasia and oxysterol levels in human lens fibers can have some interests and constitute an alternative to surgery at least at early stages of the disease.

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          Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL.

          Cholesterol biosynthesis is among the most intensely regulated processes in biology. Synthetic rates vary over hundreds of fold depending on the availability of an external source of cholesterol. Studies of this feedback regulatory process have a rich history. The field began 75 years ago when Rudolf Schoenheimer measured cholesterol balance in mice in a bottle. He found that cholesterol feeding led to decreased cholesterol synthesis, thereby introducing the general phenomenon by which end products of biosynthetic pathways inhibit their own synthesis. Recently, cholesterol feedback has been explained at a molecular level with the discovery of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs), and an appreciation of the sterol-sensing role of their partner, an escort protein called Scap. The key element in Scap is a hexapeptide sequence designated MELADL (rhymes with bottle). Thus, over 75 years, Schoenheimer's bottle led to Scap's MELADL. In addition to their basic importance in membrane biology, these studies have implications for the regulation of plasma cholesterol levels and consequently for the development of atherosclerotic plaques, myocardial infarctions, and strokes. In this article we review the major milestones in the cholesterol feedback story.
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            Cholesterol, the central lipid of mammalian cells.

            Despite its importance for mammalian cell biology and human health, there are many basic aspects of cholesterol homeostasis that are not well understood. Even for the well-characterized delivery of cholesterol to cells via lipoproteins, a novel regulatory mechanism has been discovered recently, involving a serum protein called PCSK9, which profoundly affects lipoproteins and their receptors. Cells can export cholesterol by processes that require the activity of ABC transporters, but the molecular mechanisms for cholesterol transport remain unclear. Cholesterol levels in different organelles vary by 5-10-fold, and the mechanisms for maintaining these differences are now partially understood. Several proteins have been proposed to play a role in the inter-organelle movement of cholesterol, but many aspects of the mechanisms for regulating intracellular transport and distribution of cholesterol remain to be worked out. The endoplasmic reticulum is the main organelle responsible for regulation of cholesterol synthesis, and careful measurements have shown that the proteins responsible for sterol sensing respond over a very narrow range of cholesterol concentrations to provide very precise, switch-like control over cholesterol synthesis. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Bile acids: Chemistry, physiology, and pathophysiology

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                Author and article information

                Journal
                J Ophthalmol
                JOP
                Journal of Ophthalmology
                Hindawi Publishing Corporation
                2090-004X
                2090-0058
                2011
                4 April 2011
                : 2011
                : 471947
                Affiliations
                1Inserm-CIT 808, CHU de Besançon, 25030 Besançon, France
                2Equipe Biochimie Métabolique et Nutritionnelle Centre de Recherche INSERM 866 (Lipides, Nutrition, Cancer), Faculté des Sciences Gabriel, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France
                3LCME/Département de Chimie, Université Paul Verlaine-Metz, 57012 Metz, France
                Author notes

                Academic Editor: Jie Jin Wang

                Article
                10.1155/2011/471947
                3090752
                21577274
                996abb42-9852-44c6-a7ab-16865a5f7659
                Copyright © 2011 Anne Vejux et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 November 2010
                : 18 January 2011
                : 10 February 2011
                Categories
                Review Article

                Ophthalmology & Optometry
                Ophthalmology & Optometry

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