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a fundamental factor in the initiation of atherogenesis. However, the process of atherosclerotic plaque formation is not a passive deposition of lipid within the arterial wall. It is a complex process which locally involves the coordinated response by immune cells and vascular smooth muscle cells to endothelial damage and lipid accumulation, in addition to the deposition of cholesterol,apoB, phospholipid and triglyceride. Physical stress in the local environment also contributes to lipid deposition. In regions of arteries where mechanical forces increase the exposure time of the lumen to lipoproteins, plaques are more likely to develop. Evidence of this is observed clinically as hypertension increases CVD risk by 2fold, independent of other risk factors. Studies in children with familial hypercholesterolemia and no other contributing risk factors, demonstrate that atherosclerosis occurs in proportion to blood lipid levels, suggesting high LDL-C is sufficient to cause disease. Arteries consist of three distinct layers: the intima (closest to the lumen of the vessel), the media and the adventitia. The inner surface of the intima is defined by endothelium while the internal elastic lamina delineates the outer surface. It contains a single layer of endothelial cells, smooth muscle cells and subendothelial connective tissue. Endotheial cells regulate vascular tone through the secretion of vasoactive substances including nitric oxide and endothelin. The media layer, defined by the external elastic lamina consists of smooth muscle cells which produce elastin, collagen and sulphated glucosaminoglycans. The adventitia or outermost layer contains collagen fibres, fibroblasts and progenitor cells. Normally, vascular endothelium prevents access to large molecules, including CE-rich LDL, however in response to endotheial dysfunction, this barrier increases adhesiveness and permeablility, allowing small, dense LDL particles to enter and accrue within the arterial intima. The upregulation of adhesion molecules including P-selectin, intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) by the endothelium encourages the extravasation of monocytes and infiltration of macrophages into the intima. Composition of the atherosclerotic arterial wall Arteries contain three distinct layers, the intima which contains a layer of endothelial cells which normally provide a barrier against the entry of cholesterol-rich LDL particles, the media, which is contains smooth muscle cells and regulates vascular tone and the adventitia, which contains collagen and proteoglycans. In this image the intima is diseased and the plaque contains lipoproteins, macrophage foam cells and lymphocytes. The plaque is covered by a dense layer of smooth muscle cells and extracellular matrix proteins to prevent contact with the blood as the contents are highly thrombogenic. Lipid homeostasis in both macrophages and smooth muscle cells is dynamically regulated by uptake, storage and efflux of cholesterol in response to sterol content within the cell. When taken up in their native form by the LDL receptor (LDLR), CE from lipoprotein particles is hydrolyzed by lysosomal acid hydrolase to free cholesterol and transported by Niemman Pick C1 (NPC1) to the endoplasmic reticulum, where, it can be reesterified and stored in lipid droplets. Alternatively, cholesterol, can be effluxed as free cholesterol through the actions of ABC transporter A1 (ABCA1) to lipid poor apolipoprotein A1 (apoA1) or by ABCG1 to HDL particles . As cholesterol accumulates in the cell, expression of the LDLR and endogenous synthesis of cholesterol will decrease, and efflux from the cell will increase. However, upon entry into the intima, LDL can be oxidized and scavenged by macrophages. Macrophage scavenger receptors, which unlike the LDLR are not regulated by negative feedback by cholesterol, are responsible for the uptake of modified LDL. They include cluster of
leading to increased leukocyte infiltration and proliferation. cholesterol can be re-esterified in the endoplasmic reticulum and stored in cytosolic lipid droplets. and function to maintain vascular integrity and tone. lipid composition and association with apolipoproteins. Atherosclerotic Lesion Characterization and Progression. Lesions can regress or complications including vessel occlusion. AV. which secrete cytokines and chemokines. LIPOPROTEINS All lipoproteins are soluble. Monocyte infiltration has been shown to be crucial in early atherogenesis as mice with reduced levels of macrophages are protected from early lesion formation. This type of lipid uptake is not regulated by the sterol content of the cell and results in the formation of macrophage foam cells. The largest lipoproteins. macrophages accumulate large amounts of lipoprotein-derived CE within lipid droplets and develop into foam cells. Cholesterol trafficking within the macrophage. Initiating events in the development of atherosclerotic lesions include endothelial dysfunction and arterial deposition of lipid and lipoproteins. Lipoprotein types are classified based on their density. Lipoprotein Classification . Initial lesions or fatty streaks are characterized by the thickening of the intima and the accumulation of macrophages and lymphocytes. Atherosclerosis is characterized as a chronic inflammatory disease. smooth muscle cells are stimulated to proliferate and they secrete and deposit extracellular matrix proteins leading to an increase in fibrous plaque.differentiation (CD) 36. ABCA1 and ABCG1 which efflux cholesterol and phospholipids to apolipoprotein A1 and high density lipoprotein (HDL) respectively. are formed in the intestine and transport dietary TG on an apolipoprotein B48 (apoB48) scaffold. Lipid homeostasis in macrophages is maintained by regulation of uptake. storage and efflux. VLDL undergoes a series of modifications and lipid exchanges to form CE-enriched LDL particles. rupture and thrombosis may occur. spherical lipid traffickers which consist of a hydrophobic triglyceride (TG) and CE core. Lipid accumulation stimulates the influx of macrophages. In order to stabilize the growing lipid core. It is through this process that earlystage lesions called fatty streaks are formed. chylomicrons. All. smooth muscle cells proliferate. Triglyceride-rich lipoprotein particles are hydrolyzed by lipoprotein lipase (LPL) and fatty acids are taken up and re-esterified into lipid droplets. They occur very early in life and may continue to develop from childhood onward or regress. which engulf the lipid leading to foam cell formation and the initiation of a fatty streak. C and E. Alternatively. accumulate lipid and secrete extracellular matrix proteins including collagen. They are also associated with apolipoproteins Al. As the lesion progresses. CD68 and scavenger receptor A l/lI (SRAI/II). CD36 and SRA l/lI. As a result. cholesterol can be effluxed from the cell through the ATP binding cassette proteins. The regulated uptake of cholesteryl ester rich lipoproteins occurs through the low density lipoprotein receptor (LDLR). Upon hydrolysis in the endosome. phospholipids and apolipoprotiens. Very low density lipoproteins (VLDL) transport endogenous TG with a modest amount of CE on an apoBIOC scaffold and interact with apoEs and apoCs. Modified LDL is taken up by the scavenger receptors. surrounded by a surface layer of free cholesterol (FC). Smooth muscle cells are normally quiescent within the arterial wall.
absorbed very efficiently in the intestine and dictates the rate of formation of TG-rich chylomicrons . It requires the condensation of two acetyl-CoA molecules to create acetoacetyl-CoA which is subsequently converted to mevalonate by HMG-CoA reductase. which is subsequently converted to cholesterol through a further 19 step process. The subsequent CE-enriched particles. Released fatty acids and glycerol diffuse through the capillary walls to be taken up and utilized or reesterified and stored by peripheral tissues. an enzyme which is secreted by parenchymal cells of muscle and adipose and resides on the capillary endothelium. Once chylomicrons enter the bloodstream. which arise from editing of the APOB mRNA transcript. IDL and LDL may also be cleared by the liver through the LDLR. which perform the bulk of liver functions and non-parenchyma! cells including endothelial cells. Squalene is cyclized to form lanosterol. ApoB exists in two isoforms. In mice. In addition to the uptake of dietary cholesterol and fatty acids. and apoCII is required for TG hydrolysis by lipoprotein lipase. The cholesteryl esterrich remnant particle is taken up by the liver through LDLR-mediated endocytosis.LIPOPROTEIN METABOLISM Whole body lipid homeostasis is maintained through a balance between exogenous cholesterol and fatty acid intake and endogenous synthesis. Both cholesterol and triglyceride synthesis begin with the formation of acetyl-CoA. involving greater than 30 individual reactions. Cholesterol from peripheral tissues is effluxed to HDL and which is also taken up by the liver through SRB1 and secreted into bile. and thus aid in the regulation of lipid uptake by the liver (Bouwens et al. apoB48 is the main isoform. Endothelial cells of capillaries in the liver allow free diffusion of small molecules between the blood and hepatocytes while filtering out larger molecules like chylomicrons. and subsequently into the blood stream. They then bind heparin sulfate proteoglycans. The lipolysis of triglycerides by lipoprotein lipase (LPL) allows fatty acid uptake into peripheral tissues. In the human intestine. . The protein scaffold for assembly of cholesterol and TG into chylomicron particles is apolipoprotein B. Through a series of condensation reactions. the liver is the primary regulator of whole body cholesterol and lipid metabolism (Hegele. Kupffer cells and other immune cells. initially into the lymphatics. while full length apoB100 is expressed exclusively in human liver.and LDL related receptor (LRP). isoprene units are formed which condense to form squalene. Dietary fat is hydrolyzed by pancreatic lipase. in addition to PL are packaged onto the apoB48 protein backbone by microsomal triglyceride transport protein (MTP) within intestinal enterocytes prior to secretion into the lymphatic system . both the liver and intestine produce apoB48. Approximately 50% of dietary cholesterol is absorbed by the intestine. EXOGENOUS LIPOPROTEIN METABOLISM Cholesterol absorption is mediated by the transporter Niemann-Pick C1-like1 (NPC1L1). 2009). they become associated with apolipoproteins E and C. TG and cholesterol.mediated recognition of apoE ENDOGENOUS LIPOPROTEIN METABOLISM Since only a small component of circulating cholesterol is derived from the diet. Endogenous and Exogenous Lipoprotein Metabolism Dietary triglycerides and cholesterol are packaged onto the apolipoprotein B48 scaffold and secreted as chylomicrons.CE rich remnant particles are taken up very efficiently by the liver through LDLR. Cholesterol synthesis is very complex. the enzyme target of statin drugs. which also undergo hydrolysis by lipoprotein lipase. ApoB48 is the N-terminal 48% of the 550 kDa polypeptide chain which is edited by apoB-encoding mRNA (apobec). The liver secretes TG-rich VLDL particles. The liver is composed of hepatocytes. derived from the metabolism of glucose or fatty acids. 1992). the endogenous synthesis of both lipids also occurs in the liver..
vegetables. apoB must be transcribed. isoflavones. is expressed 19 ubiquitously and can mediate peripheral lipoprotein uptake. HEPATIC LIPOPROTEIN SYNTHESIS In order to be successfully secreted into plasma.. dense LDL particles. new therapies are required.Most studies have focused on the ability of flavonoid rich foods to modulate endothelial function. The LDLR. properly folded and glycosylated. In light of the increasing prevalence of this disease. In the search for new targets and interventions to improve risk factors and prevent the complications of atherosclerosis. Epidemiological studies have established an inverse relationship between flavonoid consumption and many chronic diseases including coronary heart disease (CHD) and stroke. flavanones. hypertension. However both the LDLR and the LDLR related protein (LRP) are expressed predominantly in liver. IDL can also be converted into LDL by further lipolysis and the addition of CE through the activity of CETP. which mediates the clearance of most lipoprotein particles from plasma (Espirito Santo et al. wine. lipidated. 2008). resulting in the conversion of VLDL into intermediate-density lipoprotein (IDL). resulting in small. fruits. lipoprotein lipase (LPL) initiates lipolysis of TG within VLDL. improved weight management and improved glucose tolerance . cocoa. which binds the apoB backbone of LDL. they can become enriched in apoE. attention has turned to non-traditional therapies including a group of naturally-occurring compounds known as flavonoid PROPERTIES OF FLAVONOIDS AND EPIDEMIOLOGIAL EVIDENCE Flavonoids are the most abundant polyphenols in the human diet and can be found in a variety of foods and beverages including soy. blood pressure and . nuts. These include flavonols.. seeds. flavan-3-ols and anthocyanidins. Lipoprotein and fatty acid uptake can play a significant role in regulating lipid levels within tissues. Increases in the intake of fruits and vegetables have also been associated with reductions in a number of risk factors for heart disease including lower blood pressure . which further reduces particle size. insulin resistance and visceral obesity for the development of type 2 diabetes and premature atherosclerosis . Thus the complexity of this process allows for multiple points of regulation during apoB particle synthesis and assembly FLAVONOIDS Metabolic syndrome is a clustering of risk factors including dyslipidemia. Within the bloodstream. Several thousand have been identified and they can be divided into groups depending on their structural variation and degree of oxidation. Assembly of the TG-rich core onto the apoB100 backbone happens exclusively in the liver and VLDL is the primary lipoprotein synthesized and secreted. 2005). coffee and tea . and fatty acid uptake via CD36 by peripheral tissues such as adipose and muscle.The synthesis of fatty acids begins when acetyl-CoA is carboxylated to form malonyl-CoA. which is subsequently elongated to palmitic acid by fatty acid synthase (FAS). flavones. Once the VLDL are reduced in size. Participants in the top tertile of flavonoid intake demonstrated a 20% risk reduction in CHD mortality compared to individuals in the lower. Both cholesterol and triglyceride availability within the liver have been shown to regulate lipoprotein secretion. which leads to uptake via recognition of apoE by the LDLR and LDLR related protein (LRP) (Hu et al. flow-mediated dilatation. These TG-enriched LDL particles are substrates for hepatic lipase. fully translated and the polypeptide translocated.
However. hypertriglyceridemia. Resveratrol also prevents lipid peroxidation and increases cholesterol . chocolate. Administration of berberine to hypercholesterolemic patients reduced LDL cholesterol by 25%. Dyslipidemia is characterized by hepatic over secretion of apoBIOO-containing lipoproteins. However. both animal and human studies have demonstrated that mixtures of specific bioactive flavonoids can decrease LDL-C. Berberine. More recently. Treatment of fructose-induced. the mechanism was not elucidated. without significantly affecting plasma cholesterol.lipids. Furthermore. variation in the bioavailability of flavonoid subclasses. Flavonoids by their structure are reducing agents and can serve as efficient chelators of transition metals involved in cellular oxidation reactions Therefore. Administration of pomegranate juice. Following 3 months of supplementation. Using the same apoE1' mouse model. This heterogeneity in response reflects. black tea. the lipid lowering properties of flavonoids have also been evaluated. in part. However. which may have stimulated LDL receptor mediated uptake of LDL from plasma . an increasingly number of studies have demonstrated that flavonoids are powerful biological agents capable of regulating many metabolic pathways through other mechanisms. blood pressure lowering. FLAVONOIDS AND ATHEROSCLEROSIS The early stages of atherosclerosis are characterized by endothelial dysfunction and macrophage foam cell formation. The mechanism for the reduction in plasma cholesterol was through a reduction in hepatic cholesterol synthesis. 4 month supplementation of a low fat diet with the polyphenolic compound resveratrol led to a reduction in total plasma cholesterol and LDL-C and an increase in HDL-C. wide variability is observed in the effects of flavonoids on these biomarkers of cardiovascular disease risk. inhibition of lipoprotein oxidation and decreased plasma concentrations of apoB100-containing lipoproteins. an alkaloid isolated from Chinese herbs. red wine and grape demonstrated no beneficial effects on LDL-C or HDL-C in human studies. However. LIPIDS AND LIPOPROTEINS In concert with their antioxidant effects. attention has turned to purified flavonoids and the examination of their pharmacological properties. delayed clearance of LDL and low levels of HDL. the most abundant flavonoids may not necessarily lead to the highest concentrations of biologically active compounds. up-regulated LDL receptor expression in cultured hepatocytes through a MAPKerk dependent mechanism and reduced plasma lipids in a hyperlipidemic hamster model. in human studies. insulinresistant hamsters with a mixture of citrus polymethoxylated flavones improved dyslipidemia and glucose tolerance. atherosclerosis was significantly reduced. However. Dietary studies in humans have demonstrated the beneficial effects of many flavonoids including those contained in soy protein isolate and green tea. Administration of pomegranate by-product (PBP) to apoE^mice also attenuated atherosclerosis development. much of the association between flavonoids and reduced CHD has been attributed to their antioxidant properties and linked to a reduction in oxidative stress. rich in anthocyanidins and proanthocyanidins to apolipoprotein E-deficient (apoE1') mice resulted in dramatic reductions in lipid peroxides and macrophage CE accumulation. studies with anthocyanidins. demonstrating the cholesterol lowering potential of berberine in humans. both of which lower LDL cholesterol. Flavonoids have the potential to prevent CVD through a number of mechanisms including improved endothelial function. FLAVONOIDS. as a result of decreased cellular uptake of oxidized LDL and macrophage oxidative stress.
In streptozotocin-induced diabetic rats. However.p. i. injection of naringenin decreased blood glucose and improved dyslipidemia. the glycoside form of naringenin found in citrus fruits. In cholesterol-fed rats. resveratrol significantly reduced atherosclerotic plaque development in the aortic arch of apoE1' mice . CITRUS FLAVONOIDS The most common flavonoids in citrus fruits investigated for potential lipid lowering include naringenin. is hydrolyzed by the intestinal microflora to the flavanone naringenin. in none of these studies was the mechanism of action elucidated. Administration of grapefruit or orange juice to hypercholesterolemic casein-fed rabbits reduced LDL-C and hepatic lipid accumulation suggesting components of citrus may have lipid lowering properties.efflux from macrophages Through these mechanisms. hesperitin. . nobiletin and tangeritin. naringenin lowered plasma cholesterol which was associated with inhibition of hepatic cholesterol synthesis and esterification . Naringin.
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