Catabolism of cholesterol

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases... 

Dextrothyroxine speeds up the decomposition of cholesterol and lipoproteins, thus activating catabolism of cholesterol in the liver, which results in cholesterol being more intensively transformed into bile salts. It lowers the level of low-density lipoproteins in the plasma and very low-density lipoproteins in fatty tissue. It is recommended for treating hyperlipoproteinemia. Synonyms of this drug are choloxin, lizolipin, natexin, travenon, and others. 

Partial ileal bypass has been used in severe heterozygous and homozygous familial hypercholesterolemia however, it is ineffective in the latter case. Ileal bypass removes the site of bile acid reabsorption, depleting the bile acid pool and increasing the catabolism of cholesterol. A randomized trial of diet versus surgery, called Program On the Surgical Control of the Hyperlipidemias (POSCH), reported... 

Mayer, D. (1976). The circadian rhythm of synthesis and catabolism of cholesterol. Arch. Toxicol. 36, 267—276. 

It seems evident that (1) if bile acid elimination is inhibited or impaired as a primary phenomenon, e.g., in biliary obstruction and hypercholesterolemia, a decreased catabolism of cholesterol leads to hypercholesterolemia and reduced cholesterol synthesis (2) if bile acid elimination is primarily augmented, e.g., after an external bile fistula, ileal bypass, ileal resection, cholestyramine treatment, or perhaps a diet rich in fibrous material, conversion of cholesterol to bile acids is enhanced, leading almost always, despite stimulated cholesterol synthesis, to a fall in serum cholesterol (3) if endogenous cholesterol production is primarily increased, e.g., by obesity and excess of calories, bile acid synthesis and elimination are augmented, preventing together with increased neutral sterol elimination in some but not all cases the increase of serum cholesterol. This suggests that removal, not production, of cholesterol is the primary factor which determines serum cholesterol level. 

An interrupted enterohepatic circulation of cholesterol itself is seen in malabsorption (119), very little extra bile salts being lost. Under these conditions, the bile acid fluxes to and from the liver are probably normal, the return of cholesterol being markedly reduced and the biliary secretion normal or increased. Thus (a) cholesterol synthesis is increased, (b) bile acid synthesis is normal or slightly elevated, and (c) serum cholesterol is low due to augmented catabolism of cholesterol via fecal neutral sterol excretion. The relationship between bile acid and cholesterol metabolism under different conditions in which cholesterol synthesis is altered is illustrated in Table I. 

Another group of hypercholesterolemic (type II) patients, indicated in Table II by the term essential hypercholesterolemia, was also studied. These patients differed from familial hypercholesterolemia patients in that the family history was less clear, serum cholesterol was less elevated, and xanthomata were not present. Hypercholesterolemia may be primarily caused by environmental, primarily dietary, factors. Bile acid production in this group is less significantly reduced than in the familial group, and the relative catabolism of cholesterol by way of bile acids is within normal limits. Sodhi (151) observed in this type of hypercholesterolemia a markedly low fecal bile acid excretion. 

In hypothyroidism, the fecal steroids tended to contain relatively more bile acids (38 %) than normally (31%), while in hyperthyroidism quite normal values were obtained. This indicates that the hypercholesterolemia found consistently in hypothyroidism is caused by a defect in the elimination of cholesterol itself, the catabolism of cholesterol via bile acids being less significantly affected. 

The major pathway of cholesterol elimination in the rat is via fecal excretion of bile acids. This pathway may be divided into two related events (a) the catabolism of cholesterol to bile acids and (b) the excretion of bile acids from the pool. Pituitary hormones may thus affect one or both of these processes. 

In animals as well as man, castration causes increased serum cholesterol levels. Androgens have variable effects on serum cholesterol, while estrogens induce a decrease (29). It has been postulated that the mechanism of action of estrogens on serum cholesterol levels might involve increased uptake of cholesterol by the Kupffer cells of the liver, with a subsequent increase in catabolism of cholesterol (30). 

Bile acid metabolism in conventional animals is the activity of a balanced ecological system composed of the host, the associated intestinal microflora, and the diet. The host contributes the bile acids themselves and serves to maintain the homeostasis of the gastrointestinal tract. The intestinal microflora alters the molecular structure of the bile acids which it comes into contact with and also profoundly alters the physiological and, to a degree, the anatomical features of the host. The diet contributes the nutrition for both the host and the intestinal microflora and can cause marked changes in the flora s activity toward the bile acids in vivo (52). In addition, the amount of dietary sterols may cause the host to change its absorption and/or catabolism of cholesterol to bile acid and thus the rate of bile acid excretion (53). 

A multitude of genetic defects lead to an increased synthesis and/or a decreased catabolism of cholesterol or LDL. A well characterized although rare defect is the LDL-receptordefect. Ascorbate deficiency unmasks these inherited metabolic defects and leads to an increased plasma concentration of cholesterol-rich lipoproteins, e.g. LDL, and their deposition in the vascular wall. Hypercholesterolemia increases the risk for premature CVD primarily when combined with elevated plasma levels of Lp(a) or triglycerides. 

The mechanisms by which ascorbate supplementation prevents the exacerbation of hypercholesterolemia and related CVD include an increased catabolism of cholesterol. In particular, ascorbate is known to stimulate 7-a-hydroxylase, a key enzyme in the conversion of cholesterol to bile acids and to increase the expression of LDL receptors on the cell surface. Moreover, ascorbate is known to inhibit endogenous cholesterol synthesis as well as oxidative modification of LDL (for review see 1). 

It is well estabhshed that serum cholesterol in hypothyroid patients is invariably elevated and then rapidly reduced after thyroid hormone administration. Using radioactive acetate and labeled cholesterol, respectively, it has been demonstrated [173] that both the biosynthesis and the rate of ehmination of cholesterol are lower than normal in hypothyroidism. It has been suggested, therefore, that catabolism of cholesterol is impaired to a greater extent than the biosynthesis of the same, so that hypercholesterolemia is the necessary consequence. Administration of thyroid hormone causes less cholesterol biosynthesis than the oxidative removal of sterols resulting in a reduction of serum cholesterol levels [173]. 

Favorable results have been reported by Hashim and van Itallie (1965) with the use of cholestyramine in EFH. This material, an anion exchange resin, as the chloride salt exchanges Cl for bile acids and thus promotes their excretion. Its hypocholesterolemic effect appears to rest on both induction of increased catabolism of cholesterol and its decreased reabsorption. The above authors treated 9 persons with EFH with daily doses averaging 13.3 gm/day for 1 month to 4 years and observed a decrease of the serum cholesterol levels to 80—50 per cent of the average control values. Xanthomas became softer and smaller. 

The research areas covered by the Meeting are very wide, having to do with the liver and biliary pathophysiology, nutrition, gallstone disease and atherosclerosis prevention. Scientists from the major clinical and basic disciplines provided an update overview of the complex mechanisms regulating the biosynthesis and catabolism of cholesterol and the formation and metabolism of bile acids. 

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