Cholesterol catabolism

Bile acid synthesis from cholesterol is the prime pathway for cholesterol catabolism. Cholesterol is converted into bile acids via multiple pathways which involve 17 different enzymes. Many of these enzymes are predominantly expressed in the liver and are localized in several different subcellular... 

Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, et al. 2001. On the turnover of brain cholesterol in patients with Alzheimer s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314 45-48. 

Pravastatin sodium besides increasing LDL cholesterol catabolism, also inhibits LDL-cholesterol production by inhibiting hepatic synthesis of VLDL-cholesterol, the LDL-cholesterol precursor. These effects result in a reduction of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apolipoprotein B and trigly-cerides, whilst increasing (HDL-cholesterol) and apolipoprotein A. It has little effect on cholesterol synthesis in other tissues. 

Colestipol Binds bile acids in gut prevents reabsorption increases cholesterol catabolism up-regulates LDL receptors Decreases LDL Elevated LDL, digitalis toxicity, pruritus Oral taken with meals not absorbed Toxicity Constipation, bloating interferes with absorption of some drugs and vitamins... 

BAs are a group of acids with a steroidal ring structure and a terminal carboxylic group located in the side chain (Fig. 5.4.1), and represent the major end products of cholesterol catabolism [2]. 

Scorbutic guinea pigs develop hypercholesterolemia, which may lead to the development of cholesterol-rich gallstones. This is largely the result of impaired activity of cholesterol 7-hydroxylase, which is an ascorbate-dependent enzyme (Section 13.3.8), resulting in reduced oxidation of cholesterol to bUe acids. There is no evidence that increased intakes of vitamin C above requirements result in increased cholesterol catabolism. 

Abstract. When experimental animals are kept on an atherogenic diet the NADPH-dependent phospholipid deoxygenase in the membranes of the hepatic endoplasmic reticulum is activated and the degree of membrane oxidation is increased. Peroxide modification of microsomal membranes is attended by changes in their conformation and as a consequence, changes in the activity of membrane-bound enzymes. Proceeding from the fact that the synthesis of the components and the assembly of the supramolecular lipoprotein structure as well as cholesterol catabolism are accomplished by the enzyme systems localized in the hepatic microsomes, the role of peroxidation of the microsomal lipids in the pathogenesis of atherosclerosis is discussed. 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

Nagaoka, S., H. Miyazaki, Y. Aoyama and A. Yoshida. Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats. Br. J. Nutr. 64 161—169, 1990. 

Bile salt molecules secreted by the gallbladder are essential for the emulsification and absorption of fats. They are the salt forms of bile acids, which are the major product of cholesterol catabolism in the liver. Bile salts form micelles as their hydrophobic face contacts the fat (triacylglycerol), and their polar face maintains contact with the aqueous enviromnent. This micelle formation allows water-soluble digestive enzymes to digest the entrapped triacylglycerol molecnle, releasing fatty acids that are readily absorbed by the digestive system. 

Russell, D.W. (1999). Nuclear orphan receptors control cholesterol catabolism. Cell 97, 539-542. 

In our laboratory, we have observed that pectin increased cholesterol ester excretion in rats fed a cholesterol-containing diet (26). An early report ( ] indicated that fecal excretion of endogenous cholesterol ester could be influenced by the type of fat. Polyunsaturated fat (com oil] as compared with saturated fat (lard] accelerated cholesterol ester, but not total cholesterol excretion (27). It was suggested that, under certain circumstances, cholesterol ester excretion was one of the major pathways of cholesterol catabolism and a process for lowering body cholesterol and might explain why corn oil lowers serum... 

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. 

In contrast to many earlier studies using less specific procedures cf, 55), the chemical methods, which apparently give the most reliable results, have shown that the daily bile acid synthesis is normally relatively low in man, being about 250 mg/day (range from about 100 to 400 mg/day), i.e., about one-third of total cholesterol catabolism. Dietary factors, and especially body size and obesity, affect the values sensitively impaired liver function and hypercholesterolemia decrease, and malabsorption, especially ileal dysfunction, increases markedly the fecal bile acid elimination (11,62,63). Determination of the fecal bile salt excretion is a sensitive method for detection of ileal dysfunction (64). 

The isotope dilution method is relatively easy to perform technically. The procedure has been widely used for measurement of cholesterol catabolism in different conditions (69-74) and of bile salt kinetics in gastrointestinal disorders (75-78). Markedly augmented loss of bile acids in ileopathy makes the procedure less reliable because the administered isotope may disappear totally into feces during the first day, sometimes even during the first enterohepatic circulation of the bile acid pool after administration of the label. Under these conditions, no quantitative figures are obtained, the method being suitable for screening of this disorder. 

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Table II shows the fecal bile salt output and the contribution of bile acids to the cholesterol catabolism in both hyper- and hypothyroid patients. The fecal bile acid excretion tended to be supernormal in hyperthyroidism, but the variation was wide because two of the patients had a mild diarrhea associated with a markedly elevated bile acid output (557 and 1480 mg/day, respectively). If these two patients are excluded, the remaining ten women had slightly elevated values, though even then the output per kilogram of body...

II. STUDIES OF CHOLESTEROL CATABOLISM TO BILE ACIDS IN GERMFREE ANIMALS... 

---