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INTRAVENOUSLY ADMINISTERED LECITHIN UPOSOMES: A SYNTHETIC ANTIATHEROGENIC UPID PARTICLE KEVINJON WILUAMS* VICTORIA P. WERTHJ andJON A. WOLFFt 1. Introduction Almost 3 decades ago, intravenous administration of lecithin was shown to induce regression of experimental atherosclerosis in rabbits [1—6]. This was confirmed by several groups using different animal models [7-9]. No satisfactory explanation for this phenomenon has been offered [4, 5, 8, 10-12]. We propose that lecithin induces regression of experimental atherosclerosis by forming a synthetic antiadierogenic lipid particle, the lecithin liposome. We are proposing the following. Intravenously injected lecithin forms circulating liposomes, which take up cholesterol from many sources, including the arterial wall. In this way, lecithin liposomes become carriers ofendogenous cholesterol. These liposomes are gradually removed from the circulation by the liver, which catabolizes liposomes and excretes their cholesterol. Mobilization and excretion of endogenous cholesterol are further enhanced by the interactions of circulating liposomes with native lipoproteins and red blood cells. For example, circulating liposomes pick up apoproteins from native lipoproteins. Apoproteins directly augment the ability of liposomes to extract tissue cholesterol and may facilitate their catabolism by the liver. In addition, liposomes remove cholesterol from, and donate phospholipid to, native lipoproteins. These modifications The authors thank Simeon Margolis and Henry Seidel of The Johns Hopkins University , Ferd E. Williams of the University of Delaware, and Anne L. Williams for their generous guidance and support. ?Department of Internal Medicine, Division of Endocrinology, Yale University, 333 Cedar Street, New Haven, Connecticut 06510. (Work done while at the University of Chicago.) tDepartment of Medicine, Northwestern University, Chicago, Illinois 60611.¿Department of Pediatrics, University of California, San Diego, California 92103.©1984 by The University of Chicago. AU rights reserved. 0031-5982/84/2703-0396$01.00 Perspectives in Biology and Medicine, 27, 3 ¦ Spring 1984 \ 417 may enhance the ability of native lipoproteins to extract cellular cholesterol and may reduce any further lipoprotein-mediated transport of cholesterol into the arterial wall. Finally, liposomes remove cholesterol from the membranes of red blood cells. Cholesterol-depleted red blood cells may act as additional intermediaries in the extraction of arterial cholesterol deposits. In die following sections, we first review die studies demonstrating regression of experimental atherosclerosis with intravenous administration of lecithin. We then examine the evidence diat lecidiin mobilizes tissue cholesterol by the formation of liposomes composed of lecithin and cholesterol, that these liposomes are disposed of by die liver, and Uiat interactions of liposomes with lipoproteins and red cells enhance these processes. Finally, we review literature from which we infer that die cholesterol of human atheromata may be susceptible to mobilization and excretion by intravenously administered liposomes. 2. Regression ofExpérimental Atherosclerosis with I.V. Lecithin The cholesterol-fed rabbit is widely used as an experimental model of atfierosclerosis. In diis model, rabbits fed on a diet containing 1-5 percent added cholesterol develop witfiin 4—12 weeks deposits of cholesterol in many tissues, including die intima of large arteries. These intimai deposits remain die same size or even progress when the rabbits are returned to their usual cholesterol-free diet [13]. In contrast, intravenous administration of lecidiin preparations of varying purity (0.53 .5 g two to three times a week) resulted in rapid, substantial regression of the intimai lesions, with resolution in 1-4 weeks or after a total phospholipid dose of about 2-12 g [1-4, 6]. Lecithin-induced regression occurred even while the rabbits were maintained on die cholesterol-rich, adierogenic diet [6]. Similar results were observed in other models. Experimental atherosclerosis produced in rabbits by a semisyndietic cholesterol-free diet rich in saturated fat regressed with infusions of lecithin [5]. In baboons, the incidence and severity of experimental atherosclerosis, induced over 6 months by combining cholesterol feeding widi injections of bovine serum albumin (to produce vasculitis and intimai injury), were significandy reduced by concurrent thrice-weekly infusions of polyunsaturated lecidiin [7]. Quail fed on a high-cholesterol diet for 3 mondis developed intimai deposits diat resolved during 3 subsequent months of intravenous lecidiin administration, despite continuation of the adierogenic diet [8]. Extravascular cholesterol deposits in the subcutaneous tissues of rats regressed witfi topical lecidiin [9]. In several of diese experimental models, polyunsaturated lecidiin from soybeans...


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