Oxidized products of cholesterol: dietary and metabolic origin, and proatherosclerotic effects (review) (original) (raw)
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OXIDIZED PRODUCTS OF CHOLESTEROL: DIETARY AND METABOLIC ORIGIN AND PROATHEROSCLEROTIC EFFECTS
Cholesterol oxidation products, termed oxysterols, are increasingly considered of potential interest in the pathogenesis of atherosclerotic lesions. Of dietary or endogenous origin, oxysterols may occur in significant amounts in low density lipoprotein (LDL) particles, especially in hypercholesterolemic subjects. They likely contribute to the uptake of modified LDL by scavenger receptors, and some of them finally accumulate in the subintimal space of major arteries; here cholesterol oxides may favor the perpetuation of a chronic inflammatory state, through their ability to trigger irreversible damage of vascular cells with consequent activation of phagocytes. Furthermore, practically all oxysterols of major pathophysiologic interest have been shown to markedly up-regulate expression and synthesis of adhesion molecules, inflammatory cytokines and chemokines. Cholesterol oxidation thus appears to be an important biochemical pathway through which it exerts toxic, inflammatory and finally atherogenic effects.
Cholesterol oxidation products in the progression of atherosclerosis
2010
Corrispondenza a: Dott. Giuseppe Poli, Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, 10043 Orbassano (Turin), Italy. Tel. 011-6705422, fax 011-6705424, e-mail: giuseppe.poli@unito.it Summary Oxysterols represent a family of 27-carbon cholesterol derivatives that may be absorbed with the diet or originated endogenously. These compounds are able to modulate various signaling pathways, by this way exerting a number of biochemical effects that include promotion of chronic inflammation, fibrosis and apoptotic cell death. Cholesterol oxidation products, as with the other oxidation products of the lipid moiety of plasma low density lipoproteins (LDL), are consistently found within the characteristic lesions of atherosclerosis. Of note, the challenge of cells of the macrophage lineage with a mixture of oxysterols like that detectable in hypercholesterolemic individuals leads to a marked overexpression of various inflammation-related molecules lik...
The Journal of Lipid Research
Early fatty streaks and advanced lesions are characterized by the deposition of cholesterol and cholesterol oxidation products (oxysterols). Oxysterols have been shown to be cytotoxic and pro-atherogenic compared to cholesterol and are found in cholesterol-rich processed foods. The consumption of dietary oxysterols may be significant in the onset and development of vascular disease. In order to study the short term effects of low levels of ingested dietary oxysterols on lipoprotein and aortic cholesterol and oxysterol levels, rabbits were fed either standard chow, chow supplemented with 1.0% oxidized cholesterol (containing 6% oxysterols), or 1.0% purified cholesterol (control). To determine the distribution and uptake of oxysterols after a 2-week dietar y period, triglyceride-rich plasma lipoproteins, low density lipoproteins and aorta were analyzed by GC-MS. The concentration of 7  -hydroxycholesterol was similar in all groups but the oxidized cholesterol-fed animals showed five times the concentration of 5 ␣ ,6 ␣ -epoxycholesterol and double the level of 7-ketocholesterol in triglyceride-rich lipoproteins compared to the purified cholesterol-fed animals. The presence of 7-ketocholesterol in LDL was exclusive to animals fed the oxidized cholesterol diet. In addition, oxidation of triglyceride-rich lipoproteins was significantly greater in rabbits fed oxidized cholesterol compared to the pure cholesterol-fed animals. The oxidized cholesterol-fed animals also had a 64% increase in total aortic cholesterol, despite lower plasma cholesterol levels compared to the pure cholesterol control animals.
Mediators of Inflammation
Objective. Oxidized cholesterol derivatives are thought to exert atherogenic effect thus adversely affecting vascular endothelium. The aim of the study was to assess the effect of 5α,6α-epoxycholesterol on experimentally induced hypercholesterolemia in rabbits, and the levels of homocysteine (HCY), asymmetric dimethylarginine (ADMA), paraoxonase-1 (PON-1), and inflammatory parameters (IL-6, TNF-α, CRP). Material and methods. The rabbits were divided into 3 groups, 8 animals each, and fed with basic fodder (C), basic fodder plus cholesterol (Ch) or basic fodder plus 5α,6α-epoxycholesterol, and unoxidized cholesterol (ECh). Serum concentrations of studied parameters were determined at 45-day intervals. The study was continued for six months. Results. We demonstrated that adding 5α,6α-epoxycholesterol to basic fodder significantly affected lipid status of the experimental animals, increasing total cholesterol and LDL cholesterol levels, as well as HCY and ADMA levels, whilst leaving th...
Alteration of Some Inflammatory Biomarkers by Dietary Oxysterols in Rats
Inflammation, 2012
Oxysterols are structurally similar to cholesterol, but are characterized by one or more additional oxygen-containing functional groups. These compounds are implicated in inflammation given their ability to cause irreversible damage to vascular cells. The aim of this study was to study the alteration of some inflammatory biomarkers in Wistar rats in response to dietary oxysterols. Eighteen rats were randomly divided into three groups of six rats each. A standard diet supplemented with 1% (w/w) pure cholesterol (Chol group) or 1% (w/w) of an oxidized cholesterol mixture (COPs group) was fed for 8 weeks. Blood serum was separated; abdominal, pericardial, and epididymal adipose tissue was removed carefully. The COPs subjects exhibited significant increase in blood pressure and serum triacylgycerols as well as increased body fat index and pericardic, abdominal, and epididymal adipose tissue. These effects were accompanied by elevated circulating levels of plasma high-sensitivity C-reactive protein, tumor necrosis factor alpha, and resistin. We suggest that dietary oxysterols have an important pro-inflammatory effect.
Comparative atherogenic effects of cholesterol and cholesterol oxides
Atherosclerosis, 1986
Previous findings indicating that the oxidation products of cholesterol are associated with atherogenicity have led to a comparative study of the subchronic effects of feeding rabbits purified cholesterol, oxidized cholesterols free of cholesterol and cholesterol esters, or a mixture of cholesterol and oxidized cholesterols. Macroscopically, the cholesterol-fed animals exhibited 6-fold more arterial lesions than the animals fed cholesterol-free oxidized cholesterols. Microscopically, there was no statistically significant difference from the control in the number of histochemically-defined lesions in any of the groups. However, the lesions in the cholesterol-fed group were more severe, as indicated by a statistically significant increase in the magnitude of the lesions. This increased severity was also characterized by greater frequency and intensity of Azure A/Thionin, VonKossa, and Horseradish Peroxidase-Wheat Germ Agglutinin staining. Electronmicroscopic studies of normal appearing arterial tissues showed an increased density of viable smooth muscle cells and an increase in vacuolar extracellular debris in the cholesterol-fed group. Oxidized cholesterols in the concentrations and relative compositions administered here are markedly less atherogenie to rabbits than highly purified cholesterol.
Aging Cell, 2008
Oxidative stress, inflammation and altered cholesterol metabolism and levels are among the pathogenetic mechanisms of cognitive impairment that may accompany aging. Within the research area of hypercholesterolemia and age-related disease processes, the molecular mechanisms of cholesterol interaction with the inflammatory cells of the macrophage lineage are yet to be elucidated. We thus investigated the effect of both non-oxidized and oxidized cholesterol on monocytic cell differentiation and foam cell formation, as it occurs within vascular lesions during progression of atherosclerosis. In vitro experiments performed on human U937 promonocytic cells showed that a biologically representative mixture of oxysterols markedly stimulated CD36 expression and synthesis. In contrast, non-oxidized cholesterol did not exert any effect on CD36 mRNA and protein levels. Furthermore, the oxysterol-induced up-regulation of CD36 appeared to be based on the subsequent activation of protein kinase Cδ δ δ δ (PKCδ δ δ δ), extracellular signal-regulated kinase 1/2 (ERK1/2) and peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ). Cells overexpressing CD36 were indeed able to actively take up oxidized low-density lipoproteins, and become foam cells. The essential role of ERK pathway and CD36 receptor in oxysterol-induced foam cell formation was proved by the prevention of the latter event when monocytic cells were incubated in the presence of MEK1/2 selective inhibitor or anti-CD36 specific antibody. These experimental findings point to cholesterol oxidation as an essential reaction for this sterol to exert cellular stress and tissue damage in age-related diseases in which inflammation represents a main driving force.
Grasas y Aceites, 2004
Productos oxidados del colesterol en alimentos: riesgos potenciales para la salud y papel preventivo de los antioxidantes. El colesterol es una molécula con un doble enlace en su estructura; por lo tanto es susceptible a la oxidación y su transformación en oxiesteroles. Estos productos de oxidación se encuentran en gran diversidad de alimentos y se forman durante la manufactura y procesamiento. Algunos de los oxiesteroles son potencialmente citotóxicos, mutagénicos, aterogénicos y carcinogénicos. Los huevos y productos derivados del huevo constituyen la principal fuente en la dieta de oxiesteroles. También se encuentran oxiesteroles en derivados lácteos y leche sometida a altas temperaturas. Carnes y patatas fritas y, en general, alimentos preparados mediante fritura con aceites vegetales/animales, son otra fuente de oxiesteroles de particular importancia en la dieta occidental. Con la intención de prevenir o reducir la oxidación del colesterol se utilizan antioxidantes sintéticos o de origen natural. Los antioxidantes no solo inhiben la oxidación de los ácidos grasos en los triglicéridos, sino que también pueden inhibir la oxidación del colesterol. Entre los antioxidantes sintéticos, 2,6-di-terciaributil-4metilfenol (BHT) y terciari butilhidroquinona (TBHQ) pueden inhibir la oxidación térmica del colesterol. Entre los antioxidantes naturales, alfa-y gamma-tocoferol, extractos de romero, y el flavonoide quercetina, son potentes inhibidores de la oxidación del colesterol. PALABRAS-CLAVE: Colesterol-Oxidación del colesterol-Oxiesteroles-Antioxidantes sintéticos-Antioxidantes naturales SUMMARY Cholesterol oxidized products in foods: potential health hazards and the role of antioxidants in prevention. Cholesterol is a molecule with a double bond in its structure, and therefore it is susceptible to oxidation leading to the formation of oxysterols. These oxidation products are found in many commonly consumed foods and are formed during their manufacture and/or processing. Concern about the consumption of oxysterols arises from the potentially cytotoxic, mutagenic, atherogenic, and possibly carcinogenic effects of some of them. Eggs and egg-derived products are the main dietary sources of oxysterols. Thermally processed milk and milk-derived products are also another source of oxysterols in our diet. Fried meats, and other miscellaneous foods, such as French fried potatoes, when prepared using vegetable/animal frying oil, are another important source of oxysterols in the western diet. Efforts to prevent or to reduce cholesterol oxidation are directed to the application of antioxidants of either synthetic or natural origin. Antioxidants cannot only inhibit triglyceride oxidation, but some of them can also inhibit c h o l e s t e r o l oxi d a t i o n. Am o n g s y n t h e ti c a n ti ox id a n t s, 2,6-di-ter tiar ybutyl-4-methylphenol (BHT) and ter tiar y bu tyl hy d r o q u in o n e (T BHQ) , c a n e ff ic i en tly in hib it the thermal-induced oxidation of cholesterol. Among natural antioxidants, alpha-and gamma-tocopherol, rosemary extracts, and flavonoid quercetin, show the strongest inhibitory action against cholesterol oxidation.
7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils
European journal of nutrition, 2015
Oxysterols are cholesterol-oxygenated derivatives generated in the organism and also present in foods because of cholesterol oxidation during processing and storage. They are the natural ligands of liver X receptors (LXRs) and are generally recognized as hypocholesterolemic and anti-inflammatory molecules although this latter property is still controversial. Most oxysterol studies have been performed in macrophages, whereas the effects of oxysterols in neutrophils are poorly known. In this study, human neutrophils were exposed to two different oxysterols, 7-keto-cholesterol (7-k-chol) and 25-hydroxy-cholesterol (25-OH-chol), and their possible participation in inflammatory process was evaluated. Human neutrophils were incubated with 7-k-chol and 25-OH-chol, and ROS production, translocation of the NADPH oxidase cytosolic components, hemoxygenase-1 (HO-1) expression and lysozyme secretion were analyzed. An increase in ROS production was observed within a short period of time (minutes...