Cholesterol and bile acids

G. Paumgartner, A. Stiehl, and W. Gerok, eds.. Bile Acids and Cholesterol in Health and Disease, MTP Press Ltd, Boston, Mass., 1983. 

Molecular Interactions. Various polysaccharides readily associate with other substances, including bile acids and cholesterol, proteins, small organic molecules, inorganic salts, and ions. Anionic polysaccharides form salts and chelate complexes with cations some neutral polysaccharides form complexes with inorganic salts and some interactions are stmcture specific. Starch amylose and the linear branches of amylopectin form inclusion complexes with several classes of polar molecules, including fatty acids, glycerides, alcohols, esters, ketones, and iodine/iodide. The absorbed molecule occupies the cavity of the amylose helix, which has the capacity to expand somewhat to accommodate larger molecules. The starch—Hpid complex is important in food systems. Whether similar inclusion complexes can form with any of the dietary fiber components is not known. 

When Reuben et al., measured the hourly secretion rates of phospholipids, bile acids and cholesterol in obese and nonobese individuals with and without cholesterol gallstone disease, they found that the pattern of results was quite different in the obese and the nonobese gallstone carriers. The obese had hypersecretion of cholesterol but normal bile-acid output, while the nonobese had normal cholesterol secretion but a reduced bile-acid output. The authors speculated that the most likely explanation for the high biliary cholesterol secretion rates in the obese was their increased total body cholesterol synthesis. Conversely, nonobese gallstone carriers often have a reduced total bile-acid pool size, and if the enterohepatic cycling frequency of this small bile-acid pool remains unchanged (controversial), it could explain the reduced bile-acid secretion rate seen in the normal weight (nonobese) individuals. 

The cholesterol excreted with the bile is poorly water-soluble. Together with phospholipids and bile acids, it forms micelles (see p. 270), which keep it in solution. If the proportions of phospholipids, bile acids and cholesterol shift, gallstones can arise. These mainly consist of precipitated cholesterol (cholesterol stones), but can also contain Ca " salts of bile acids and bile pigments (pigment stones). 

Dietary fiber has a pronounced effect on the characteristics of the fecal mass and on the rate of passage of digest through the G1 trad, High fiber diets also play a role in the excretion of bile acids and cholesterol. 

Fig. 7. Induction of Cyp7al gene expression by oxysterol-activated LXRa RXRa. Both the bile acid and cholesterol biosynthetic pathways generate oxysterols. The binding site of LXRaiRXRa in the Cyp7al gene promoter is a DR-4 element (a direct repeat of the hexanucleotide hormone response element separated by 4 nt).

The estrogen receptor-subtype ERa mediates the hepatotoxicity of 17a-ethinylestradiol (EE2). Upon EE2 treatment, ERa represses the expression of bile acid and cholesterol transporters (bile salt export pump, BSEP), Na /taurocholate cotransporting polypeptide (NTCP), OATPl, OATP2, ABCG5, and ABCG8 in the liver [101]. The genetic variability of some of these transporters is well known and could explain, at least in part, the interindividual differences for the tolerability of oral contraceptives. 

Biochemical evidence of liver damage (increased blood glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GRT], glutamate dehydrogenase [GDH], bile acids, and cholesterol), as well as hepatocellular enlargement and vacuolation, were observed in rats exposed to 154 mg... 

An understanding of the mechanisms by which the compensatory increase in bile acid and cholesterol synthesis takes place following interrupted enterohepatic circulation of bile acids would be important not only... 

This raises a question of whether the mechanism of stimulated bile acid production during interrupted enterohepatic circulation of bile acids is different from that found during the enhanced cholesterol production in obesity. It is reasonable to assume that in obesity the biliary secretion of both bile acids and cholesterol is augmented and that subsequent intestinal reabsorption from the expanded intraluminal pool is increased in absolute figures (probably decreased relatively). Thus the fluxes both of bile acids via the portal blood and of cholesterol via the lymphatics back to the liver are augmented. Despite these two fluxes, from which the former at least is supposed to inhibit bile salt production (and cholesterol synthesis as well), the hepatic synthesis of bile acids is actually increased, suggesting that it is an increased cholesterol synthesis which stimulates bile acid production. 

In interrupted enterohepatic circulation, the biliary secretion of both bile acids and cholesterol is decreased and their reabsorption reduced, so... 

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. 

Serum cholesterol is usually markedly elevated in biliary obstruction, with especially high values in biliary cirrhosis. A positive correlation is found occasionally (196) but not constantly (193) between the serum bile acid and cholesterol levels. An absence of bile acids in the gut lumen and a reduced cholesterol absorption may stimulate, at least initially, both intestinal and hepatic cholesterol production cf. 92,223), and this in association with a block in elimination both as bile acids and as cholesterol itself rapidly raises the serum cholesterol level. However, in biliary obstruction of long duration, e.g., in biliary cirrhosis, sterol balance studies and urinary bile acid measurement indicate that cholesterol synthesis is markedly reduced (88). In parenchymal cell damage of the liver, the serum cholesterol is normal or decreased, probably because the hepatic cholesterol synthesis, due to cell injury, is reduced in proportion to, or proportionally more than, the decreased cholesterol elimination (11,182) and, furthermore, intestinal and hepatic cholesterogenesis may still be under the partial feedback control of bile acids and absorbed cholesterol, respectively. 

The liver is an important organ for lipoprotein metabolism. It is not only a major site of lipoprotein synthesis, but also the most important site of lipoprotein catabolism. Most of the apolipoproteins, as well as the cholesterol and cholesterylester moieties of all circulating plasma lipoproteins, are catabolized in the liver. This makes sense because the liver is the only organ capable of degrading substantial amounts of cholesterol. The resulting bile acids are secreted in the bile, together with undegraded cholesterol. A small part of the bile acids and cholesterol escapes the enterohepatic circulation and forms the major route of cholesterol excretion from the body. 

Lithocholic acid was first isolated from a gallstone by Fischer in 1911 (30). It was later isolated from ox bile (1 g from 100 kg of bile) (64) from rabbit bile (0.4 g from 900 ml) (65) and subsequently from monkey, human, pig, and guinea pig bile (2, 66, 67). Lithocholic acid has been identified as one of the bile acids in human blood (68) and as a principal fecal bile acid. Moset-tig et al. (69) isolated lithocholic acid from human stool and estimated its concentration to be 3 g/100 kg of fresh stool. Lithocholic acid is particularly insoluble, is not hydroxylated to an appreciable extent in man (70), and may be the cause of liver disease (4). In early studies lithocholic acid was not available in sufficient amounts from natural sources and was prepared from cholic acid. Lithocholic acid was particularly valuable in establishing the correspondence of the B/C ring structure between bile acids and cholesterol (71). 

Carulli, Effect of thyroid function on hepatic sterol metabolism in man. Proceedings of the 7 International meeting on Bile acids and cholesterol in health and disease , Basel (1982). 

Table 2. Serum lipids, fecal bile acids and cholesterol synthesis before and after cholestyramine treatment in patients with different types of hyperlipoproteinemias. Mean-SE. 

Type III hyperlipoproteinemia may be associated with increased VLDL production and abnormal elimination of VLDL remnants. Bile acid and cholesterol synthesis appear to be within normal limits. However, the use of the isotopic technique has indicated that bile acid production is about twice that in hyperlipoproteinemia type II and is not different from that in type IV. 37 cholesterol synthesis may have been within the... 

Primary type IV hyperlipoproteinemia is associated with enhanced VLDL production and/or impaired VLDL removal and caused mostly by familial hypertriglyceridemia or combined hyperlipoproteinemia. There has been a lot of discussion on a causative association between enhanced VLDL production and bile acid and cholesterol synthesis. U i6 23 Some evidence has also been presented that a primary change in bile acid and cholesterol synthesis would alter secondarily VLDL synthesis. 

Despite quite high basal bile acid production the response of bile acid and cholesterol synthesis to cholestyramine is not excessively high in type IV (Table 2). Cholic acid which is predominantly increased in type IV appears to respond quite little to cholestyramine (cf. 8). 

Table 3. Correlation of bile acid and cholesterol synthesis with serum lipids and triglyceride metabolism in two families (n = 17) with familial hypertriglyceridemia...

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