**3. Atherosclerosis and CVD**

Atherosclerosis is a disease of the arterial wall that is characterized by cholesterol accumulation and culminates in potentially life-threatening conditions such as heart attack, stroke and angina. The build-up of cholesterol in the walls of arteries is a hallmark of atherosclerosis. However, the process starts is poorly understood. The atherogenic process starts at an early age with the deposition in blood vessel walls of lipids such as cholesterol, derived from lipoproteins circulating in the bloodstream, which leads to the formation of the characteristic 'fatty streaks'. Inflammatory white blood cells congregate at these damaged areas through their interaction with adhesion molecules expressed by cells in the endothelial layer, which lines the inside of blood vessels. This event then sets off a cascade of inflammatory process and further lipid deposition, leading eventually to full blown atherosclerosis with plaque forma‐ tion in the artery wall. Atherosclerosis is thus viewed as a chronic inflammatory disease of the blood vessel wall [34], [35]. Oxidized LDL contributes to atherogenesis and is an early event of atherosclerosis. WhenLDL particles become trapped in an artery, they can undergoprog‐ ressive oxidation and be internalized by macrophages bymeans of the scavenger receptors on the surfaces of these cells. The internalization leads to the formation of lipid peroxidesand facilitates the accumulation of cholesterol esters, resultingin the formation of foam cells. As the fatty streak progresses, smooth muscle cells (not normally present in the subendothelial space) migrate from the media to the subendothelial space where they proliferate and produce connective tissue to form a fibrous cap, which represents the second phase of atherosclerosis. Finally, complicated lesions occur, which can manifest calcification, hemorrhage, ulceration and thrombosis [35, 36]. All these changes and events lead to the hardening and thickening of artery wall, reducing or blocking blood flow. Atherosclerosis is a silent and asymptomatic disease until complications arise with thrombosis and occurrence of clinical symptoms [37]. The clinical manifestation of atherosclerotic plaque formation is acute vascular occlusion due to the formation of a thrombus or clot which can lead to ischemia of vital organs, such as heart causing myocardial infarction, brain resulting in strokes and lower extremites causing peripheral artery disease. Oxidized LDL contributes to atherothrombosis by inducing endo‐ thelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages [38]. It is reasonably thinking that maintaining a healthy cholesterol or lipid profile is critically important to the health cardiovascular system.

#### **4. Cholesterol homeostasis**

Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of essential functions in the body. For example, cholesterol is a structural component of cell membranes and modulates cell membrane fluidity; cholesterol is a precursor of bile acids, steroid hormones and vitamin D. It is therefore of critical importance that the cells of the body be assured a continuous supply of cholesterol. To meet this need, a complex series of transport, biosynthetic and regulatory mechanism has evolved. The liver plays a central role in the regulation of the body's cholesterol homeostasis. For example, cholesterol enters the liver's cholesterol pool from a number of sources including dietary cholesterol, as well as cholesterol synthesized de novo by extra hepatic tissues as well as by the liver itself. Cholesterol is eliminated from the liver as unmodified cholesterol in the bile or it can be converted to bile acids that are secreted in bile into the intestinal lumen.

Cholesterol, similar with other lipids (triacylglycerols and phospholipids) do not circulate as independent molecules but are carried by specific apolipoproteins to form macromo‐ lecular complexes, called lipoproteins. Plasma lipoproteins keep their component lipids soluble during circulation and provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. Four major groups of lipoproteins have been identi‐ fied and they are important physiologically and in clinical diagnosis. They are chylomi‐ crons, very low density lipoproteins (VLDL or pre β lipoprotein), LDL (β lipoprotein) and HDL (α lipoprotein). They differ in their relative composition of cholesterol, triacyl‐ glyceroles, phospholipids and apoproteins.

Chylomicrons, the largest and least dense lipoproteins, predominately transport triacyl‐ glycerols to adipose tissue and muscle, but also deliver the absorbed dietary and billiary cholesterol to the liver. Once most of the triacylglycerols have been delivered to the adi‐ pose tissue and muscle, the remnants of the lipoprotein, including cholesterol, apo-E, and apo-B48 are then delivered to and taken up by the liver through interaction with the chy‐ lomicron remnant receptor.

VLDL is smaller and more dense than chylomicrons. VLDL contains triacylglycerols, some cholesterol and cholesteryl esters and the apoproteins; apo-B100, apo-CI, apo-CII, apo-CIII, and apoE. VLDL delivers triacylglycerols and cholesteryl esters from the liver and distribute them throughout the body. When VLDL moves into the circulating blood, it is converted first to intermediate density lipoproteins (IDL) and then into low density lipoproteins (LDL). Lipoprotein lipase serves to remove the majority of fatty acids from both the VLDL and IDL, thus increasing the density of the lipoproteins while maintaining cholesterol and cholesteryl ester concentrations. The removal of fatty acids and the loss of all apolipoproteins except apoB-100 and apo(a) results in the formation of LDL.

LDL is the primary blood carrier of cholesterol and delivers cholesterol to all tissues. LDL can be absorbed by the liver and other tissues via receptor mediated endocytosis. The LDL receptor recognizes the main apolipoprotein of LDL, apo-B100, resulting in the intake of LDL and subsequently enzymatic hydrolysis of cholesteryl ester. A positive cor‐ relation exists between the incidence of coronary atherosclerosis and the plasma concen‐ tration of LDL cholesterol.

High density lipoprotein is the smallest but most dense lipoproteins in the body. Nascent HDL or HDL contains several types of apolipoproteins including apo-AI, II & IV, apo-CI, II & III, apoD and apoE. HDL contains protein, phospholipids, cholesteryl esters, and cholesterol. HDL is produced as a protein-rich particle in the liver and intestine, and serves as a circulating source of Apo-CI & II and ApoE proteins. The HDL protein particle accumulates cholesteryl esters through the esterification of cholesterol by lecithin:cholesterol acyl-transferase (LCAT). LCAT is activated by apo-AI on HDL. HDL returns the liver where cholesterol is removed by reverse cholesterol transport, thus, serving as a scavenger of free cholesterol. Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from HDL to VLDL, IDL, and LDL in exchange of triacylglycerol, relieving the inhibition of LCAT activity in HDL.
