Cholesterol conversion to bile acids

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Homig, D., and Weiser, H., 1976, Ascorbic acid and cholesterol Effect of graded oral intakes on cholesterol conversion to bile acids in guinea-pigs, Experientia 32 687-689. 

Pig, i. Some steps in the sequence of the cholesterol conversion to bile acid conjugates ... 

Whether changes in the composition of the diet influence the conjugating enzyme activity directly or only influence the conjugation capacity by means of changes of the substrate supply to the liver is so far not known. Xor have any unequivocal results been presented which answer the question as to whether the bile acid conjugation reaction has any importance for the regulation of the rate of cholesterol conversion to bile acids. 

About 1 g of cholesterol is ehminated from the body per day. Approximately half is excreted in the feces after conversion to bile acids. The remainder is excreted as cholesterol. Coprostanol is the principal sterol in the... 

The ring structure of cholesterol cannot be metabolized to C02 and HfeO in humans. Rather, the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, and by secretion of cholesterol into the bile, which transports it to the intestine for elimination. Some of the cholesterol in the intestine is modified by bacteria before excretion. The primary compounds made are the isomers coprostanol and cholestanol, which are reduced derivatives of cholesterol. Together with cholesterol, these compounds make up the bulk of (neutral fecal sterols. 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

In the liver, cholesterol has three major fates conversion to bile acids, secretion into the blocKlstream (packaged in lipoproteins), and insertion into the plasma membrane. Conversion of cholesterol to cholic acid, one of the bile acids, requires about 10 enzymes. The rate of bile synthesis is regulated by the first enzyme of the pathway, cholesterol la-hydioxylase, one of the cytochrome P450 enzymes (see the section on Iron in Chapter 10), Cholesterol, mainly in the form of cholesteryl esters, is exported to other organs, after packaging in particles called very-low-density lipoproteins. Synthesis of cholesteryl esters is catalyzed by acyl CoA cho-Jesteroi acy(transferase, a membranc bound enzyme of the ER, Free cholesterol is used in membrane synthesis, where it appears as part of the walls of vesicles in the cytoplasm. These vesicles travel to the plasma membrane, where subsequent fusion results in incorporation of their cholesterol and phospholipids into the plasma membrane. 

The cholesterol that is used throughout the body is derived from two sources diet and de novo synthesis. When the diet provides sufficient cholesterol, the synthesis of this molecule is depressed. In normal individuals cholesterol delivered by LDL suppresses cholesterol synthesis. Cholesterol biosynthesis is stimulated when the diet is low in cholesterol. As described previously, cholesterol is used as a cell membrane component and in the synthesis of important metabolites. An important mechanism for disposing of cholesterol is conversion to bile acids. 

Cholesterol in blood plasma is conjugated with other fipid molecules and with carrier proteins. These fipoprotein complexes may form droplets called chylomicrons, but cholesterol is usually transported as part of a number of larger lipoproteins, including low density lipoprotein (LDL), which carries cholesterol from the fiver to muscle and other tissues, and high density fipoprotein (HDL), which carries cholesterol to the fiver for conversion to bile acids. Physicians are especially concerned when patients have high levels of LDL (the so-called bad cholesterol) in blood moderate exercise and... 

Cholesterol molecules once formed in the body or absorbed from the diet can be eliminated from the human organism primarily by the gastrointestinal route as such or after conversion to bile acids. The latter are synthesized exclusively in the liver via a series of reactions which are initiated by 7a-hydroxylation of cholesterol (1). Bile acids subsequently formed are called primary bile acids, in contrast to secondary bile acids, which are formed by intestinal microorganisms from the primary ones during the enterohepatic circulation. 

In hypophysectomized rats, the synthesis of cholesterol from acetate (19,20)—but not from mevalonate (21)—is inhibited, indicating that pituitary hormones have an effect on a metabolic step between acetate and mevalonate, probably on hydroxymethylglutaryl-coenzyme A reductase. In terms of tissue cholesterol concentrations, the hypophysectomized rat differs little from the normal. Although bile acid synthesis and excretion are reduced, these animals reach a steady state in which normal cholesterol concentrations in plasma and tissue are maintained (21,22). This is true, however, only when the hypophysectomized rat is maintained on a low-cholesterol diet. When cholesterol intake is increased, both serum and tissue cholesterol reach high levels, presumably because of the decreased ability of the hypophysectomized rat to eliminate that sterol by conversion to bile acids (10, 11,23). 

According to Gordon et al. (1957) the unsaturated fatty acids lower the plasma cholesterol in man by an increased conversion to bile acids and fecal excretion of the latter. Lewis (1958) confirmed this in studies in three pa-... 

There are several hypotheses to explain the NSP action on plasma cholesterol, including enhanced bile acid and neutral sterol excretion, the slowing of fat and cholesterol absorption and direct inhibition of hepatic cholesterol synthesis by propionate formed by large bowel fermentation of NSPs. Whole body cholesterol homoeostasis represents a balance between influx and loss. Cholesterol influx can come from dietary intake and de novo synthesis. Losses occur through the sloughing of epithelial cells and through the fecal excretion of nonabsorbed dietary cholesterol and biliary steroids (bile acids and neutral sterols). Bile acids are generally recovered in the ileum, and those that are not absorbed are excreted in the feces. Any increase in bile acid excretion leads to enhanced hepatic uptake of cholesterol and its conversion to bile acids with a consequent depletion of the plasma cholesterol pool. 

Questran, which is colestyramine, binds to bile acids resulting in prevention of their re-absorption and hence promoting hepatic conversion of cholesterol into bile acids. 

The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in derepression of 7-a-hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid-sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2). 

They are useful only in hyperlipoproteinemias involving elevated levels of LDL i.e. type Ila, lib and V. They are basic ion exchange resins. They are neither digested nor absorbed in the gut. They bind bile acids in intestine and interrupt their entero-hepatic circulation, leading to increased faecal excretion of bile salts and cholesterol. There is increased hepatic conversion of choles-terol to bile acids. More LDL receptors are expressed on liver cells leading to increased clearance of IDL, LDL and indirectly of VLDL. 

The conversion of cholesterol to bile acids is quantitatively the most important mechanism for degradation of cholesterol. In a normal human adult approximately 0.5 g of cholesterol is converted to bile acids each day. The regulation of this process operates at the initial biosynthetic step catalyzed by an enzyme in the endoplasmic reticulum, la-hydroxylase (fig. 20.18). The 7a-hydroxylase is one of a group of enzymes called mixed-function oxidases, which are involved in the hydroxylation of the sterol molecule at numerous specific sites. A mixed-function oxidase is an enzyme complex that catalyzes hydroxylation of a substrate with a concomitant production of H20 from a single molecule of 02- The 7a-hydroxylase is one of several enzymes referred to as cytochrome P450. 

Impairment of bile acid absorption and consequent loss of these acids via excretion presumably causes an increase in hepatic conversion of cholesterol to bile acids. This conversion lowers serum cholesterol, particularly when serum contains high levels of cholesterol derived from dietary intake. However, when fed with a cholesterol-free diet, 10% pectin supplementation stimulated a 3-fold increase in cholesterol biosynthesis (77). Biosynthesis of phospholipids and triglycerides also increased significantly hence, it was suggested that these increases occurred in response to diminished fat absorption occasioned by pectin intake. This compensatory biosynthesis of cholesterol and lipids may account for pectin s inability (in most cases) to lower serum cholesterol levels in animals fed cholesterol-free diets. 

A major pathway by which LDL are catabolized in hepatocytes and other cells involves receptor-mediated endocytosis. Cholesteryl esters from the LDL core are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by de novo synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via remnants of VLDL and chylomicrons. Thus, the liver plays a major role in the cholesterol economy. Unlike other cells, hepatocytes are capable of eliminating cholesterol by secretion of cholesterol in bile and by conversion of cholesterol to bile acids. 

Increased fatty acid catabolism decreases the concentration of free fatty acids available for export from the liver as circulating triglycerides. This provides a rationale for the lowered triglyceride values. The lowered serum cholesterol concentration apparently results from inhibition of cholesterol synthesis and stimulation of the conversion of cholesterol to bile acids in the liver (Nair and Kurup 1986). 

An opposite effect is at the basis of the up-regulation of LDL receptors in response to treatments with bile acid sequestrants, intestinal cholesterol absorption inhibitors, and HMG-CoA reductase inhibitors. The first class of drugs inhibits the intestinal reabsorption of bile acids, thus promoting increased conversion of cholesterol to bile acids in the liver. The increased demand for cholesterol results in activation of the SREBP system and upregulation of LDL receptor synthesis (as well as cholesterol synthesis via upregulation of HMG-CoA reductase). Similarly, inhibition of intestinal cholesterol absorption with ezetimibe results in a reduction in the hepatic cholesterol pool... 

Mass spectrometry has become an indispensable method for the analysis of bile acids by virtue of its power to identify, assign structure and quantify free or conjugated bile acids, either pure or in mixtures. It is useful not only to study the metabolism of bile acids but also for the detection and diagnosis of metabolic diseases. Indeed, numerous metabolic diseases resulting from an alteration of the conversion of cholesterol to bile acids have been described, including peroxisomal disorders resulting in a block of (3-oxidation of the lateral chain and other enzyme deficiencies interfering with the biochemistry of the side chain or the steroid nucleus. 

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