Bile acids production

Duane WC, Gilberstadt ml Wiegand DM (1979) Diurnal rhythms of bile acid production in the rat. Am J Physiol 236 R175-R179... 

Bile acid production amounts to 400-500 mg/day (ca. 1 mmol). Excretion in the stool is of a similar order accordingly, renewed synthesis of bile acids is determined by the daily loss. Excretion in the urine lies below 0.5 mg/day (8 gmol/day) - this small amount may be disregarded. 

Hoekstra R, Nibourg GA, van der Hoeven TV et al (2013) Phase 1 and phase 2 drug metabolism and bile acid production of HepaRG cells in a bioartificial liver in absence of dimethyl sulfoxide. Drug Metab Dispos 41 562-567... 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

Vitamin K is essential for successful formation of many clotting factors so lack of vitamin K can cause a coagulation disorder. Normal bile acid production is necessary for absorption of vitamin K from the small intestine. 

Despite being inhibitors of the cytochrome P450 isoenzyme CYP3A4, the protease inhibitors do not appear to alter mefloquine pharmacokinetics. It was suggested that the decrease in ritonavir levels was due to decreased absorption, perhaps due to mefloquine-induced inhibition of bile acid production or induction of P-glycoprotein. ... 

Animal experiments, in particular, have been useful in testing various hypotheses about the relative effectiveness of different kinds of dietary fiber and about possible mechanisms of fiber effects. Thus, studies of bulking action (9-10), of selective secondary bile acid binding (11-12), of increased intestinal transit times (13), of altered bacterial activities and secondary bile acid production (14-19), and selective binding of carcinogens (16-19) have been carried out in laboratory animals. Several related studies have been conducted in humans as well. Among the latter are investigations of the relationship between the bulk fiber content of diets and fecal bile acids or other steroids (4.20-21). 

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. 

Elimination of cholesterol from the human body takes place primarily by the fecal route as bile acids and neutral sterols, viz. cholesterol, coprosta-nol, and coprostanone. About one-third of cholesterol is normally catabo-lized by way of bile acids (11). As will be shown later, the amount of the latter depends on the body size, so that the weight correlates with the fecal bile acids, the average daily output of 250 mg corresponding to about 4 mg/ kg. The factors regulating hepatic bile acid production under normal conditions are, however, unknown in many respects. 

There is no direct evidence so far that the actual concentration of serum cholesterol would determine bile acid production and elimination in man. For instance, increase of serum cholesterol by dietary cholesterol is not associated with compensatory increase in bile acid production (63,71,86,87). This does not exclude the possibility that an increase of some lipoprotein subfraction would stimulate bile acid synthesis. Thus determinations of bile acid synthesis by the isotope dilution method have shown markedly high values in triglyceridemic subjects (69), though according to sterol balance data this association is mostly determined by the degree of obesity of these patients (11,63). It is also interesting to note that though the serum cholesterol level and bile acid production are not normally correlated with each other, bile acid synthesis and the serum cholesterol pool are closely correlated in normocholesterolemic nonobese and obese subjects and in hypercholesterolemic individuals (88). 

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. 

Augmented Bile Acid Production Subsequent to Increased Cholesterol Synthesis... 

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. 

Normocholesterolemic women (without obesity) excrete and synthesize distinctly smaller amounts of bile acids than males (63) (Table II). The sex difference, however, almost disappears when the values are expressed per kilogram of body weight, though even then the bile acid production tends to be higher in males (4.20 0.27 mg/kg) than in females (3.27 0.31 mg/kg). Thus the possibility of an actual sex difference in bile acid metabolism is not excluded. Furthermore, women tend to eliminate slightly less cholesterol in the form of bile acids (28 % of balance) than men (33 %). Table II shows bile acid production in both sexes as measured by fecal analysis in various conditions with abnormalities in lipid metabolism. 

Since it is quite apparent that augmented bile acid synthesis is a primary phenomenon which leads to increased fecal bile acid excretion in obesity, the bile acid pool should also be large. Unfortunately, measurement of pool size has not yet been performed in relation to body weight or obesity. Enhanced bile acid production in obesity seems not to be an irreversible phenomenon. Thus weight reduction in a few overweight patients brought cholesterol synthesis and also bile acid production down to almost normal limits (136 see Fig. 2). 

TABLE II. Bile Acid Production as Measured by Fecal Excretion in Different Clinical Conditions... 

It is apparent that both the quantity and quality of the diet affect bile acid production. Both have been insufficiently studied in man, though more attention has been paid to the effects of different types of fats on fecal bile acid elimination. 

As already discussed, obesity is associated via augmented cholesterol synthesis with an increased bile acid production. Since obesity as such is a result of excessive consumption of calories, it is logical to infer that overeating stimulates cholesterol synthesis and secondarily bile acid production. An increased number and quantity of daily meals may, however, change under these conditions the metabolism of both cholesterol and bile acids in complicated ways which are not yet completely understood, by augmenting the number of enterohepatic circulations of bile salts. Increased intestinal contents and fecal mass may also interfere with reabsorption of bile acids. 

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. 

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