Atherosclerosis Free cholesterol

The primary developmental mechanism of the atherosclerotic process is not completely understood. It seems likely that the development of atherosclerosis is preceded by metabolic abnormalities of the synthesis, transport, and utilization of lipids. Lipids such as triglycerides and cholesterol esters are circulated in the blood in the form of particles (lipoproteins) wrapped in hydrophilic membranes that are synthesized from phospholipids and free cholesterol. Cholesterol is transported by particles of various sizes synthesized from triglycerides, cholesterol esters, and phospholipids, each of which plays a very specific role. 

Intestinal acyl-CoA cholesterol acyltransferase (ACAT-2, also present in liver), which esterifies free cholesterol with palmitic or oleic acid, is another enzyme that was identified early on as a potential target to inhibit cholesterol absorption because most cholesterol in chylomicrons is esterified before being secreted by enterocytes (6, 14). As for CEL, various inhibitors of this enzyme were also developed and tested with mixed results (10, 15-17). However, the importance of ACAT-2 was later confirmed by studies of gene-knockout mice, which exhibit markedly reduced cholesterol absorption and atherosclerosis when fed Western diet (18). Nonetheless, progress in developing effective ACAT inhibitors has been slow, in part because of concerns about the potential for deleterious systemic effects resulting from inhibition of the more widely expressed ACAT-1 (19). Despite these... 

The lipidome profile of mice liver homogenates of free cholesterol, low cholesterol, and high cholesterol diets showed the influence between dietary cholesterol intake and atherosclerosis (17). To get individual metabolite fingerprints, they measured near 300 metabolites such as di- and triglycerides, phosphatidylcholines, LPCs, and cholesterol esters in plasma samples by LC-MS/MS. It was observed that when dietary cholesterol intake was increased, the liver compensated for elevations in plasma cholesterol by adjusting metabolic and transport processes related to lipid metabolism, which... 

The only receptor-mediated uptake process regulated in macrophages involves suppression of )8-VLDL receptors. This suppression only occurs after extensive cholesterol ester accumulation and can be induced by either j8-VLDL or chemically modified LDL [13]. Lipoprotein uptake by all known receptor systems in macrophages causes a marked stimulation of ACAT activity which results in the massive accumulation of cholesteryl ester droplets in the cytoplasm [13]. Free cholesterol can be excreted from the macrophage if cholesterol-accepting Upoproteins such as HDL are present. The uncontrolled uptake and deposition of cholesteryl esters in macrophages is believed to be the key to formation of the foam cells which are associated with atherosclerosis. 

Tabas, L, Marathe, S., Keesler, G.A., Beatini, N., Shiratori, Y. 1996. Evidence that the initial up-regulation of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response that prevents cholesterol-induced cellular necrosis. Proposed role of an eventual failure of this response in foam cell necrosis in advanced atherosclerosis. J Biot. Chem. 271 22773-22781. 

Panasenko, O. M., Vol nova, T. V., Azizova, O. A., and Vladimirov, Y. A. (1991). Free radical modification of lipoproteins and cholesterol accumulation in cells upon atherosclerosis. Free Radical Biol. Med. 10, 137-148. 

HDL is considered to be the good cholesterol, because it accepts free cholesterol from peripheral tissues, such as cells in the walls of blood vessels. This cholesterol is converted to cholesterol ester, part of which is transferred to VLDL by CETP, and returned to the liver by IDL and LDL. The remainder of the cholesterol is transferred directly as part of the HDL molecule to the liver. The liver reutilizes the cholesterol in the synthesis of VLDL, converts it to bile salts, or excretes it directly into the bile. HDL therefore tends to lower blood cholesterol levels. Lower blood cholesterol levels correlate with a lower rates of death of atherosclerosis. 

All serum Tipids, which consist of free cholesterol, glycerides, cholesterol ester and phospholipids, circulate in association with specific proteins (apo-lipoproteins) to form lipid-protein complexes. These macromolecular complexes are called "lipoproteins" and have remarkable hydrophilic properties, in spite of high lipid contents. Therefore, water insoluble lipids are transported from their organs for synthesis to their sites for utilization. Most serum lipoproteins have a molecular weight range from approximately 200,000 to 10,000,000 and contain from 40 % to 95 % of lipids. Studies of the factors affecting lipoprotein levels are very important for health and diseases, because lipoprotein levels are closely related to atherosclerosis and its clinical manifestations. 

Rikitake Y, Kawashima S, Takeshita S etal. (2001) Anti-oxi-dative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 154 87-96 Riley PA (1994) Free radicals in biology oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 65 27-33... 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

The standard diet used in our experiments is a semipurified, cholesterol-free preparation that is composed of 25% protein, 40% sucrose, 13% coconut oil, 1% corn oil, 15% cellulose, 5% mineral mix, and 1% vitamin mix. This diet has been shown to induce an endogenous hypercholesterolemia and lead to atherosclerosis in rabbits and monkeys (4, 5). The specific question addressed by our series of investigations is whether the type of dietary protein, when all other dietary components are constant, can influence the development of hyperlipoproteinemia and atherosclerosis. More specifically, we have examined the effects of the individual amino acids, lysine and arginine, and their ratios in the diet on plasma and hepatic lipids as well as the development of arterial plaques. 

Bises, and D. M. Klurfeld. Experimental atherosclerosis in rabbits fed cholesterol-free diets. Atherosclerosis 1982 41(2-3) 279-284-... 

Patient Population. The proband of the B family, T.B., was referred to the Lipid Research Clinic at The Johns Hopkins Hospital at the age of five years because of hypercholesterolemia of 900 mg/100 ml. She had multiple planar xanthomas that had first appeared at three years of age. The patient was free of symptoms of ischemic heart disease. The index lipoprotein pattern was type lib (57), with marked hypercholesterolemia, hyperbeta-lipoproteinemia, a mild hyperprebetalipoproteinemia and hypertriglyceridemia. None of the relatives of T.B. had xanthomas or corneal arcus one (J.S.) developed signs of premature coronary atherosclerosis at the age of 43 years. Increased total plasma and LDL cholesterol levels were transmitted over three generations on both maternal and paternal sides of the family (Fig. I). The parents of the proband, S.B. and K.B., had endogenous hypertriglyceridemia as well. Two normolipidemic members of this family (S.B., Jr. and E.B.), were also studied. 

Studies of Kritchevsky et al. (1989) on experimental atherosclerosis in rabbits fed cholesterol-free diets revealed a greater influence of animal protein and of partially hydrogenated soybean oil on development of atherosclerosis than plant protein and unsaturated soybean oil. 

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