BCHS-4361-09-TANGIER_39559

BCHS-4361-09-TANGIER_39559 - TANGIER DISEASE AND REVERSE...

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TANGIER DISEASE AND REVERSE CHOLESTEROL TRANSPORT Tangier Disease is a very rare genetic disorder, which was first described in 1961. Since then, about 100 cases have been reported. Most striking symptom is enlarged, yellow-orange tonsils. A fraction of patients also have hepatomegaly and peripheral neuropathy. Symptoms are rather variable. In all Tangier patients, plasma HDL is nearly undetectable and its proteins, apo-A1 and apo-AII are reduced to very low levels. LDL levels are decreased ca. 40%. Total cholesterol is about 50% of normal. In cultured biopsied skin fibroblasts, cholesterol and phospholipids fail to exit cells and combine with exogenous lipid- free apolipoproteins. Mutations are found in the ABCA1 gene for the ATP-binding cassette transporter protein (=CERP) which is responsible for efflux of cholesterol and phospholipid from cells.
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CHARACTERISTICS OF TANGIER DISEASE: •Hypertrophic orange-colour tonsils •Very low levels of HDL in the plasma •An enlarged liver and spleen •Premature coronary artery disease
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Surface Monolayer Surface Monolayer Phospholipids (25%) Free Cholesterol (7%) Free Cholesterol (7%) Protein (45%) Protein (45%) Hydrophobic Core Hydrophobic Core Triglyceride (5%) Triglyceride (5%) Cholesteryl Esters (18%) (18%) CE Rich: HDL Cholesterol and Atherosclerosis, Grundy)
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HIGH DENSITY LIPOPROTEIN (HDL) • Smallest of the lipoproteins • Synthesized by intestine and liver as nascent cholesterol-poor lipoprotein • Accumulates cholesterol and cholesterol esters through interactions with peripheral cells and other lipoproteins • Participates in reverse cholesterol transport, which is removal of excess cholesterol from peripheral cells and delivery to the liver for metabolism
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STRUCTURE OF HDL HDL has the same essential structure as LDL, with a surface monolayer of phospholipids and free cholesterol and a hydrophobic core consisting mainly of cholesteryl esters but also some triglyceride. However, HDL particles are smaller and contain different apolipoproteins, mainly apo A-I and apo A-II. Both these apolipoproteins have properties that protect the lipids against oxidative modification. In addition, some of the other proteins transported by HDL, such as paraoxonase, have antioxidant properties. Therefore, whereas LDL is very susceptible to oxidative modification, HDL is relatively resistant to it, and this is one of the reasons underlying the anti-inflammatory properties of HDL. HDL undergoes dynamic remodeling and therefore is heterogenous in particle size or density, as well as apo composition.
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Cholesterol and Atherosclerosis, Grundy) HDL is secreted in a discoidal form from the liver and gut. As it acquires cholesterol
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BCHS-4361-09-TANGIER_39559 - TANGIER DISEASE AND REVERSE...

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