Tissue Cholesterol Synthesis

Cholesterol biosynthesis occurs in every nucleated cell in the body. Although it is often thought that the majority of cholesterol synthesis occurs in the liver, studies have shown that the bulk tissues of the body account for the overwhelming majority of endogenous cholesterol production. Hepatic cholesterol synthesis in humans is thought to contribute 10-20% of the total daily synthesis rate. Since the majority of cholesterol synthesis in the body occurs in extrahepatic tissues, and since the only quantitatively significant site for excretion and catabolism of cholesterol is the liver, approximately 600-800 mg of cholesterol each day must be transported from peripheral tissues through the plasma compartment to the liver to account for daily cholesterol cata-bolism and binary secretion. Approximately 9 mg cholesterol per kilogram body weight is synthesized by peripheral tissues every day and must be moved to the liver for catabolism via a process termed 'reverse cholesterol transport' (RCT).

RCT describes the metabolism, and important anti-atherogenic function, of the HDL-mediated efflux of cholesterol from nonhepatic cells and its subsequent delivery to the liver and steroidogenic organs for use in the synthesis of lipoproteins, bile acids, vitamin D, and steroid hormones. A cellular ABC transporter (ABCA1) mediates the first step of RCT involving the transfer of cellular cholesterol and phospholipids to lipid-poor apolipoproteins. Lecithin:cholesterol acyltransferase-mediated esterification of cholesterol generates spherical particles that continue to expand with ongoing cholesterol esterification and phospho-lipid transfer protein-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles when CETP facilitates the transfer of cholesteryl esters from HDL onto apoB-containing lipoproteins. The scavenger receptor B1 (SR-B1) promotes selective uptake of cholesteryl esters into liver and steroidogenic organs, whereas hepatic lipase- and LPL mediate hydrolysis of phospholipids and triglycerides. SR-B1 mediates the selective uptake of cholesteryl esters from HDL and also LDL into hepatocytes and steroid hormone-producing cells without internalizing HDL proteins, which can recycle through the RCT sequence moving cholesterol from peripheral tissues to the liver.

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