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Cholesterol Homeostasis

BioFiles 2007, 2.7, 1.

BioFiles 2007, 2.7, 1.

Cholesterol is an essential biological molecule that performs many functions within the body. It is a structural component of all cell membranes and is also a precursor to steroid hormones, vitamin D, and bile acids that aid in digestion. Within membranes the cholesterol to polar lipid ratios affect stability, permeability, and protein mobility. The hormones produced from cholesterol include androgens, estrogens, and the gluco- and mineralocorticoids.

Cholesterol levels in the body are achieved via two sources. Adults with healthy diets will biosynthesize the majority of their cholesterol in the liver and other body tissues and obtain the remainder from the dietary intake of foods high in saturated fatty acids. Free cholesterol is not found in blood; rather it is esterified to fatty acids and packaged in lipoprotein particles. Very low density lipoproteins (VLDL) are produced by the liver and consist of an outer core composed of apolipoproteins; apo-B100, apo-CI, apo-CII, apo-CIII, and apoE surrounding an inner core of phospholipids, triglycerides, cholesterol, and cholesteryl esters. In the blood, VLDL transfers apolipoprotein-CII to high density lipoprotein (HDL) and lipoprotein lipase in the capillaries begins to remove the triglycerides, transforming the particle into an intermediate density lipoprotein (IDL). About 50% of IDL particles are removed from the circulation by the liver. The remaining IDLs are transformed to low density lipoprotein particles (LDL, the so-called “bad” cholesterol) by the loss of apolipoprotein E and the further reduction of triglyceride content until it is exceeded by the content of cholesteryl esters. LDL particles deliver lipids to the body’s cells via LDL receptor-mediated endocytosis. When LDL lipids are oxidized by free radicals, they bind more easily to the proteoglycans lining the vascular endothelium, and thus, become incorporated into atherosclerotic plaque.

HDL, the so-called “good” cholesterol is composed of apolipoproteins-CII and E surrounding a lipid core. HDL particles circulate through the capillaries collecting lipids including cholesterol and cholesteryl esters and returning them to the liver for further metabolism. Cholesterol returned to the liver by HDL is synthesized into bile acids. Bile acids facilitate the digestion of lipids by acting as emulsifying agents and also aid in the absorption of fat-soluble vitamins. Cholesterol is ultimately excreted from the body as bile acids.

Excessive levels of oxidized LDL in the blood can lead to potential health risks. Normally cholesterol levels are tightly controlled by complex mechanisms. When dietary intake of cholesterol is high, biosynthesis is reduced. However, the body’s homeostatic mechanisms can be inadequate when baseline endogenous cholesterol biosynthesis becomes excessive or when dietary cholesterol intake is overwhelming. For these instances, drugs have been discovered that can reduce cholesterol biosynthesis (statins), reduce the intestinal absorption of dietary cholesterol and other lipids (ezetimibe), or enhance the metabolic utilization of lipids in the liver (fibrates). These drugs serve to keep the blood levels of LDL in check to avoid the deleterious effects that can arise from the accumulation of vascular plaque, including such serious medical conditions as atherosclerosis, coronary artery disease, and stroke.

This issue of BioFiles highlights the product groups that Sigma offers to further the research of cholesterol absorption, biosynthesis, transport, and excretion. We introduce two key research tools in the HMG-CoA Reductase enzyme and assay kit. We also showcase a number of important cholesterol lowering molecules including statins, sterols, and stanols.

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