**5. Hyperlipidemia and causes**

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

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

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‐

Chylomicrons, the largest and least dense lipoproteins, predominately transport triacyl‐ glycerols to adipose tissue and muscle, but also deliver the absorbed dietary and billiary

or lipid profile is critically important to the health cardiovascular system.

186 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

**4. Cholesterol homeostasis**

in bile into the intestinal lumen.

glyceroles, phospholipids and apoproteins.

Hyperlipidemia, most common form of dyslipidemia, refers to elevation of lipoproteins and/ or lipids. HDL, LDL, and VLDL vary in their atherogenicities. High levels of cholesterol particularly LDL cholesterol together with low levels ofHDL cholesterol increase the risks for developing atherosclerosis [39]. Hyperlipidemia itself usually causes no symptoms but can lead to the development of symptomatic vascular disease, including coronary artery disease and peripheral arterial disease. There are two different types of hyperlipidemia, primary and secondary hyperlipidemia:

**1.** Primary hyperlipidemia is generally due to genetic causes, such as a mutation in a receptor or binding protein. This type of hyperlipidemia is often linked to family history. For instance, defects in the essential components of lipid transportation and metabolism inherited from family. Examples include familial defect in LDL receptor or apo B-100 (diminished LDL clearance and hypercholesterolemia), familial lipoprotein lipase deficiency (hypertriglyceridemia), and combination of multiple unknown defect and known familial defects (combined hyperlipidemia).

**2.** Secondary hyperlipidemia arises due to other underlying causes, such as sedentary lifestyle coupled with the excessive dietary intakes of saturated fat, cholesterol and transfats, in addition to many other disease conditions and drug uses. These factors include obesity, diabetes mellitus, hyperhomocystinemia, smoking, alcohol intake, chronic kidney disease, hypothyroidism, primary biliary cirrhosis and other cholestatic liver diseases, and drugs, such as thiazides, β-blockers, retinoids, estrogen and progesterons, and glucocorticoids.
