_______________________________________ Hyperlipidemias and Atherosclerotic Cardiovascular Disease
the enterocyte, free cholesterol is esterified to cholesteryl esters by the enzyme acyl-CoA cholesterol acyltransferase isoform 2 (ACAT2) and incorporated into chylomicrons [54]. In a separate pathway, after enzymatic hydrolysis, free fatty acids and monoacylglycerides are transported to the intestinal cells in bile-salt micelles. Micelles deliver the lipid molecules to the enterocyte, and bile salts remain in the lumen, where they are subsequently re-used to form new micelles. Intracellularly, lipid molecules are re-assembled and packaged in chylomicrons. These are large lipoproteins (75–1,200 nm in diameter) rich in triglycerides and cholesterol but poor in protein content. Chylomicrons are released by exocytosis into the extracellular space, enter the lymphatics, and ultimately reach the bloodstream. Circulating chylomicrons are transformed by lipoprotein lipase, an enzyme expressed in endothelial cells of the capillaries in muscle and adipose tissue, and deliver triglycerides to the muscle (for energy) and adipose tissue (for storage). Chylomicron remnants deliver the cholesterol and the remaining triglycerides to the liver, where cholesterol is used in the synthesis of bile salts and triglycerides and free fatty acids are used in the production of energy by β-oxidation and synthesis of new molecules of cholesterol. The synthesis of cholesterol in hepatocytes is known as the endogenous pathway. It is relevant to mention that unesterified cholesterol can also be transported back into the intestinal tract by selective transporters, such as the ATP-binding cassette transporters ABCG5 and ABCG8 [55]. A new generation of lipid-lowering drugs that stimulate the ATP-binding cassette transporter is being investigated [56]. Endogenous Pathway In addition to their exogenous (dietary) sources, triglycerides and cholesterol esters are synthesized endogenously by the liver. The hepatic pathway is the major source of cholesterol in the body. It is well-established that daily cholesterol synthesis in the liver has a circadian pattern, with lowest levels in the day (30% to 35%) and highest levels at night (65% to 70%). This diurnal rhythm in cholesterol synthesis is regulated by HMG-CoA activity [240]. Selective inhibitors of HMG-CoA reductase, such as statins, effectively prevent the synthesis of cholesterol and are powerful hypolipidemic drugs [31; 57]. Newly formed cholesterol molecules can either be transiently stored in the hepatocytes or further transformed either into bile salts, steroids, or “packaged” in lipoproteins. These lipoproteins, which carry cholesterol and triglycerides from the liver into the circulation, are known as very-low density lipoproteins (VLDL) and have a very high content in triglycerides and cholesterol. VLDLs comprise 15% to 20% of the total blood cholesterol and most of the circulating triglycerides [31; 52]. Within the liver, enzymatic modifications in VLDL also generate LDL, which functions to transport
hepatic cholesterol to distant organ target cells for energy and for use in hormone synthesis and maintaining the integrity of cell membranes. LDL cholesterol can also be oxidized, rendering it capable of being endocytosed. Accumulation of oxidized LDL cholesterol within macrophages creates the foam cells that contribute to formation of atherosclerotic plaque. In the liver, cholesterol is also eliminated by biliary secretion in the form of bile acids. Bile acids, which are highly soluble in water, are released by the hepatocytes into the biliary canaliculi and then transported to the gallbladder, where they are stored in bile and later released into the lumen of the small intestine. Most bile acid molecules (>95%) are not excreted in the feces, but rather are reabsorbed in the ileum, enter the portal circulation, and are then extracted with high first-pass efficiency by hepatocytes. This process of recycling bile acids between liver and intestine is known as enterohepatic circulation. In fact, recycled cholesterol from bile acids is a major source of cholesterol and represents 75% of the total cholesterol that goes through the intestine; dietary cholesterol, even in patients with rich diets, accounts only for up to 25%.
AN OVERVIEW OF LIPOPROTEINS
STRUCTURE AND MOLECULAR COMPONENTS Triglycerides and cholesterol are non-polar lipids that are virtually insoluble in water. To facilitate their transport in plasma and lymph, they are packaged as lipoproteins. These large spherical macromolecules that transport cholesterol and triglycerides in the plasma vary in size (ranging from 5–1,200 nm in diameter) and density (determined by the ratio of lipid to protein content). Lipoproteins have a hydrophobic core of non-polar triglycerides and cholesteryl ester (a form of cholesterol linked by an ester bond to a fatty acid) surrounded by a monolayered shell of more water-soluble phospholipids, non-esterified cholesterol, and amphipathic surface proteins known as apoproteins. Apoproteins (also known as apolipoproteins) are a family of surface proteins that perform three important functions in lipid physiology: stabilize the structure of the lipoprotein shell, activate enzymes in the plasma and endothelial cells, and bind to selective cell receptors [27; 30; 31; 58]. Specific apoproteins regulate the metabolic fate of lipoproteins; their role can be compared to “molecular zip codes” that determine the destination of specific lipoproteins in the body. Each type of lipoprotein contains one or more specific types of apoproteins. There are four major classes of apoproteins: Apo A, Apo B, Apo C, and Apo E. In terms of clinical relevance, the following lipoproteins are the most important: Apo A-I, Apo A-II, Apo B-100, Apo C, and Apo E [27; 31].
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