Cholesterol extrahepatic synthesis

TG are derived directly from the diet and secreted from the intestines (primarily by way of the lymph) as CM and TRL or synthesized into VLDL in the liver. The net transport of TG is therefore from the intestines and the liver to skeletal and cardiac muscle or to adipose tissue for storage. Cholesterol is used for membrane synthesis and steroid production and is primarily synthesized in extrahepatic tissues. It is continuously transported between the liver, intestines, and extrahepatic tissues, but the net transport of cholesterol is from the extrahepatic tissues to the liver and intestines from where it is eliminated. 

Elevation of cholesterol is found in fatty liver, particularly under diabetic metabolic conditions. A rather marked increase in cholesterol can be observed in all forms of cholestasis differentiation between intra- or extrahepatic cholestasis, however, is not possible. This elevation of cholesterol in obstruction is due to an enhanced synthesis of cholesterol in hepatocytes and intestinal walls as well as to the retention of bile lipids. Marked elevations of cholesterol are detectable in primary biliary cirrhosis and in cholesterol storage disease. A pronounced increase in cholesterol is also found in Zieve s syndrome (L. Zieve, 1958). 

LDL, the major cholesterol transport lipoprotein, having virtually only apolipoprotein B-lOO, is mostly derived from VLDL catabolism and cellular synthesis. When fasting and when normal subjects are on low-fat intake, most cholesterol is synthesized and used in the extrahepatic organs, whereas most of the cholesterol carried by LDL is taken up by the liver for catabolism. In patients with homozygous familial hypercholesterolemia, enhanced synthesis of LDL may occur because LDL clearance is reduced as a consequence... 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

J. M. Andersen, S. D. Turley, and J. M. Dietschy, Relative rates of sterol synthesis in the liver and various extrahepatic tissues of normal and cholesterol-fed rabbits, Biochim. Biophys.Acta, 711 421-430 (1982). 

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