Contrasting effects of water-soluble and water-insoluble dietary fibers on bile acid conjugation and taurine metabolism in the rat

The effect of the type of dietary fiber on the bile acid and taurine metabolism was examined in rats. Diets containing 10% of various water-soluble fibers (citrus pectin, konjak mannan, guar gum) as compared to a fiber-free diet increased biliary excretion of total bile acids. In contrast, water-insoluble dietary fibers (cellulose, corn bran, chitin; 10% in the diets) as well as cholestyramine (5% in the diet) considerably, decreased bile acid excretion. Water-soluble dietary fibermediated increases in bile acid excretion were totally attributable to increases in glycine-conjugates. Thus, these fibers greatly increased by the bile acid glycine-to-taurine ratio (G/T). Excretio of glycine conjugates decreased more than that of taurine conjugates in rats fed various water-insoluble dietary fibers. As a results, G/T in rats fed water-insoluble fibers was significantly lowered as compared to G/T in animals fed a fiber-free diet. Cholestyramine did not affect the G/T ratio of bile acids. Fecal bile acid excretion and the activities of hepatic cholesterol 7α-hydroxylase (EC 1.14.13.17) in rats fed various water-soluble dietary fibers approximately doubled as compared to the respective values for rats fed a fiber-free diet. Whereas cholestyramine greatly increased these parameters, water-insoluble fibers did not significantly affect them. Various water-soluble fibers decreased hepatic concentration and urinary excretion of taurine as well as the activity of hepatic cysteine dioxygenase (EC 1.13.11.20). In contrast, water-insoluble fibers considerably increased hepatic taurine concentrations and enzyme activities. The parameters for taurine metabolism were unaffected by cholestyramine. It was suggested that the types of dietary fiber affected hepatic taurine synthesis and thus modified bile acid glycine/taurine ratios.     

Effects of bile acid feeding on hepatic deoxycholate 7α-hydroxylase activity in the hamster

In order to investigate the effects of bile acid feeding on hepatic microsomal deoxycholate 7α-hydroxylase activity, three different bile acids were administered (0.2% w/w in chow) to hamsters for two weeks. Deoxycholate 7α-hydroxylase activity was increased markedly by feeding of cholic acid (CA) and slightly by deoxycholic acid (DCA) Chenodeoxycholic acid (CDCA) had little effect on the enzyme activity. Feeding each of the bile acids significantly inhibited the activity of cholesterol 7α-hydroxylase in the order CDCA≥ DCA>CA. There was no correlation between deoxycholate 7α-hydroxylase activity and cholesterol 7α-hydroxylase activity. It is concluded that the activity of deoxycholate 7α-hydroxylase is up-regulated by feeding DCA and CA and that the mechanism seems to be different from that of cholesterol 7α-hydroxylase. The increased activity of hepatic deoxycholate 7α-hydroxylase by CA and DCA should be beneficial in minimizing the toxic effects of DCA in the hamster.     

Effects of perturbations in hepatic free and esterified cholesterol pools on bile acid synthesis,cholesterol 7α-hydroxylase,HMG-CoA reductase,acyl-CoA:Cholesterol acyltransferase and cytosolic cholesteryl ester hydrolase

Effects of expansion of the hepatic free cholesterol pool on bile acid and cholesterol metabolism and homeostasis were examined in rats fed cholesterol in high-fat diets or treated with oleyl-p-(n-decyl)-benzenesulfonate (ODS) or progesterone. Cholesterol feeding for 10–16 days, which increased free (33%) and esterified (6-fold) cholesterol, had no effect on cholate synthesis, total bile acid synthesis, or cholate turnover, whereas these activities were increased 60–80% by ODS and progesterone, which produced only small increases (19%) in free cholesterol. Cholesterol feeding reduced β-hydroxy-β-methylglutaryl (HMG)-CoA reductase (72%) and cholesteryl ester hydrolase (48%) and increased acyl-CoA:cholesterol acyltransferase (184%), whereas ODS and progesterone reversed these compensatory responses in cholesterol-fed rats. Cholesterol 7α-hydroxylase was changed no more than 22% by any treatment. A bolus of ODS elevated biliary cholesterol output 41% and shifted biliary bile acid synthesis and composition toward 12-deoxy bile acids. These effects were not seen in ODS-fed or progesterone-treated rats, in which cholesteryl ester stores were depleted. It is concluded that effects of free cholesterol on bile acid synthesis and biliary cholesterol are probably mediated by specific precursor or regulatory pools which can be independently regulated and which represent a relatively small fraction of hepatic free cholesterol.     

Effects of cholesterol feeding to maternal rats on metabolism of cholesterol and bile acids in the dams and their offspring

The influence of feeding cholesterol to rats during pregnancy and postpartum (from the 11th day of gestation to the third day after delivery) on the serum and hepatic cholesterol levels and on the bile acid composition in the pool and in the liver in relationship to the dams and their pups was examined. The hepatic content of cholesterol in both dam and offspring increased during cholesterol feeding without any changes in serum cholesterol level. In the dams, mainly the esterified cholesterol was increased; in the pups, mainly the free cholesterol was increased. Cholesterol feeding led to a pronounced increase in the pool of β-muricholic acid and a relative decrease in the lithocholic acid concentration in pregnant rats. In fetal rats, the chenodeoxycholic acid pool was increased by cholesterol intake. The lithocholic acid pool was larger in the postpartum rats fed cholesterol than in the controls, while the concentration of α- and β-muricholic acids was decreased. The neonates of cholesterol-fed dams had a larger pool of chenodeoxycholic acid but a smaller pool of β-muricholic acid. These results suggest that the metabolism of cholesterol and of bile acids in dams and their offspring respond differently to cholesterol intake.     

Effect of cholesterol and cholestyramine feeding and of fasting on sterol synthesis in the liver,ileum, and lung of the guinea pig

The effects of feeding diets containing either cholesterol (0.24% w/w) or cholestyramine (2.5% w/w) and of fasting on sterol synthesis in the liver, ileum, and lung of both male and female guinea pigs have been studied by measuring the incorporation by tissue slices of¹⁴C-labeled acetate into total digitonin-precipitable sterols. Cholesterol feeding significantly decreased (P<0.05) sterol synthesis in the liver, ileum, and lung of the males and in the ileum of females. Cholestyramine feeding stimulated the rate of hepatic sterol synthesis 13-fold but did not significantly affect sterologenesis in the ileum. Sterol synthesis in the lung was significantly increased (P<0.05) but to a much lesser extent than in the liver. Fatty acid synthesis in the liver, ileum, and lung was not significantly affected by either cholesterol or cholestyramine feeding. In guinea pigs fasted for 24 hr, sterol synthesis was inhibited in all three tissues, the most pronounced effect occurring in the liver. Only in the lung was fatty acid synthesis significantly decreased (P<0.001) by fasting. Cholesterol feeding resulted in increased concentrations of cholesterol in the plasma and liver. Cholestyramine feeding reduced plasma cholesterol concentration by 81% in females and by 64% in males. However, it did not significantly change the tissue cholesterol concentrations. Fasting resulted in a significant increase (P<0.05) in plasma cholesterol concentration but did not affect the concentration of cholesterol in the tissues. It was concluded that in the normal guinea pig, the feedback inhibition produced by both cholesterol and also possibly by bile acids suppresses sterol synthesis in the liver to very low rates compared to those in the small intestine, where sterologenesis is not only less sensitive to the cholesterol negative feedback system than that in the liver, but also is not subject to regulation by the bile acid negative feedback system.     

Species-dependent responsiveness of serum cholesterol to dietary proteins

Substitution of casein for soybean protein in the diet causes high degrees of hypercholesterolemia in rabbits. When rats or humans were fed exactly the same diets, no response of the concentration of serum cholesterol to the type of protein was observed. The hypothesis is put forward that, in rabbits, dietary casein and peptides derived from it—because of their high degree of phosphorylation—inhibit the binding of glycine-conjugated bile acids to insoluble calcium phosphate in the intestinal lumen. As a result, feeding of casein causes an increase in the availability of bile acids, which leads to enhanced absorption of bile acids and cholesterol. Eventually, the concentration of serum cholesterol will be increased. In rabbits this cascade of events occurs because these animals have a relatively low activity of intestinal alkaline phosphatase, and a high ratio of glycine to taurine in conjugated bile acids. Unlike glycine conjugates, taurine-conjugated bile acids do not effectively bind to the intestinal calcium-phosphate sediment. The low activity of intestinal alkaline phosphatase in rabbits secures the high degree of phosphorylation of casein and its peptide products in the small intestine. In contrast with rabbits, rats and humans have high activities of intestinal alkaline phosphatase and a low glycine-to-taurine ratio in conjugated bile acids. Thus the hypothesis presented would explain why rabbits, but not rats and humans, are susceptible to dietary casein with respect to the concentration of serum cholesterol. The relevance of the hypothesis as to the mechanisms underlying the hypercholesterolemic effect of some other dietary proteins is discussed.     

Effect of chitosan feeding on intestinal bile acid metabolism in rats

The effect of chitosan feeding (for 21 days) on intestinal bile acids was studied in male rats. Serum cholesterol levels in rats fed a commercial diet low in cholesterol were decreased by chitosan supplementation. Chitosan inhibited the transformation of cholesterol to coprostanol without causing a qualitative change in fecal excretion of these neutral sterols. Increased fiber consumption did not increase fecal excretion of bile acids, but caused a marked change in fecal bile acid composition. Litcholic acid increased sigificantly, deoxycholic acid increased to a leasser extent, whereas hyodeoxycholic acid and the 6β-isomer and 5-epimeric 3α-hydroxy-6-keto-cholanoic acid(s) decreased. The pH in the cecum and colon became elevated by chitosan feeding which affected the conversion of primary bile acids to secondary bile acids in the large intestine. In the cecum, chitosan feeding increased the concentration of α-,β-, and ω-muricholic acids, and lithocholic acid. However, the levels of hyodeoxycholic acid and its 6β-isomer, of monohydroxy-monoketo-cholanoic acids, and of 3α, 6ξ, 7ξ-trihydroxy-cholanoic acid decreased. The data suggest that chitosan feeding affects the metabolism of intestinal bile acids in rats.     

Effects of dietary cholesterol upon bile acid metabolism in guinea pig

Cholesterol fed guinea pigs develop a hemolytic anemia accompanied by high cholesterol concentrations in the liver, plasma, and red cells. We have studied the bile acid metabolism of guinea pigs fed a diet with or without cholesterol in a search for the factor(s) which prevent adequate control of their body cholesterol pool and, therefore, its pathological consequences. The results show that in the cholesterol fed guinea pig the synthesis (and excretion) of bile acids was at least three times greater than in controls. This is the result of a doubling of the fractional turnover rate and a smaller increase in the pool size. The major increase of the bile acid pool was in the liver. The main bile acid in gall bladder bile and small intestines was chenodeoxycholic acid, with smaller amounts of 7-ketolithocholic and ursodeoxycholic acids. In the caecum, large intestines, and feces, the major bile acid was lithocholic acid.     

Quantification of lowered cholesterol oxidation in guinea pigs with latent vitamin C deficiency

Fifty-two male guinea pigs fed on a scorbutigenic diet were divided into a control group (10 mg ascorbicacid per animal per day) and a group with latent vitamin C deficiency (2 weeks on the scorbutigenic diet only, followed by a maintaining dose of 0.5 mg ascorbic acid per animal per day). After 13 weeks, 26-¹⁴C-cholesterol was administered intraperitoneally to all the animals, in which the¹⁴C excretion in the expired CO₂ and the urine and cholesterol specific activity in the blood serum and liver were then studied at intervals of 24 hr and 1, 3, 5, 7, 9 and 11 weeks. The ascorbic acid concentration in the liver and spleen of the control animals was five times higher than in vitain C-deficient animals. The total cholesterol concentration in serum and liver was significantly higher in the vitamin C-deficient guinea pigs. A two-pool analysis of the disappearance curves of serum cholesterol specific activity showed that the size of the cholesterol pool A (blood and tissues with rapid cholesterol exchange) was greater in the vitamin C-deficient animals. The rate of the transformation of cholesterol to bile acids was estimated as the ratio of¹⁴CO₂ expired to liver cholesterol specific activity. Latent vitamin C deficiency caused significant slowing down of this process (controls: 11.8±0.6; vitamin C deficiency: 8.3±0.4 mg/24 r/500 g w/w). A significant correlation between the liver ascorbic acid concentration and the rate of cholesterol transformation to bile acids was found. The results demonstrate that ascorbic acid is necessary for a normal course of cholesterol catabolism. In latent vitamin C deficiency, the rate of cholesterol catabolism slows down and cholesterol consequently accumulates in the blood and liver of vitamin C-deficient guinea pigs.     

Dietary phospholipid alters biliary lipid composition in formula-fed piglets

Plasma cholesterol, arachidonic acid (AA, 20∶4n−6), and docosahexaenoic acid (DHA, 22∶6n−3) are higher in breast-fed infants than in infants fed formula without cholesterol, AA, or DHA. This study investigated differences in plasma, hepatic, and bile lipids and phospholipid fatty acids, and expression of hepatic proteins involved in sterol metabolism that result from feeding formula with cholesterol with egg phospholipid to provide AA and DHA. For this study, three groups of piglets were evaluated: piglets fed formula with 0.65 mmol/L cholesterol, the same formula with 0.8% AA and 0.2% DHA from egg phospholipid, and piglets fed sow milk. Piglets fed the formula with phospholipid AA and DHA had higher plasma high density lipoprotein, but not apoprotein (apo) B cholesterol or triglyceride; higher bile acid and phospholipid concentrations in bile; and higher liver and bile phospholipid AA and DHA than piglets fed formula without AA and DHA (P<0.05). Hydroxy methylglutaryl (HMG)-CoA reductase and 7-α-hydroxylase, the rate-limiting enzymes of cholesterol and bile acid synthesis, respectively, and low density lipoprotein receptor mRNA levels were not different between piglets fed formula without and with phospholipid AA and DHA, but HMG-CoA reductase and 7α-hydroxylase mRNA were higher, and plasma apo B containing lipoprotein cholesterol was lower in all piglets fed formula than in piglets fed milk. These studies show that supplementing formula with AA and DHA from egg phospholipid alters bile metabolism by increasing the bile AA and DHA, and bile acid and phospholipid.     

Increased biliary calcium in cholesterol and pigment gallstone disease: The role of altered bile acid composition

The present study was undertaken to define the relationship between calcium metabolism and bile acid composition in animal models of diet induced cholesterol and pigment gallstones. Groups of prairie dogs were fed either a control non-lithogenic chow (N=12), a 1.2% cholesterol enriched chow (N=6, XOL) for two weeks, or a high carbohydrate diet deficient in iron (N=6, CHO-FeD), or a high carbohydrate diet with normal iron levels (N=6, CHO) for eight weeks. Hepatic (HB) and gallbladder (GB) bile samples were analyzed for total calcium, cholesterol, phospholipids, total bile acids (TBA), and individual bile acid composition. In each of the four groups, TBA concentrations were essentially similar and taurine conjugates accounted for approximately 90% of TBA in HB bile and about 98% in GB bile. In the control group, cholic acid (CA) was the predominant bile acid and comprised 76% of TBA and chenodeoxycholic (CDCA) accounted for about 13% of the total. Feeding a diet rich in cholesterol caused a significant change in the relative concentrations of individual bile acids of hepatic bile—such that CA decreased significantly (p<0.001) while CDCA increased by 300% (p<0.001). The changes in secondary bile acids were insignificant. An identical shift in individual bile acid composition was noted in animals maintained on high carbohydrate diet, irrespective of iron content. Similar changes were observed in the GB in the experimental groups. Calcium concentrations of GB bile with or without gallstone formation showed a positive linear relationship with TBA (y=4.35+0.14X, p<0.001) and taurochenodoxycholic acid (TCDCA) (y=15.04+0.46X, p<0.001), but an inverse relationship with taurocholic acid (TCA) (Y=55.16−0.41X, p<0.008). However, such relationships were absent in hepatic bile. These data indicate that diet-induced alterations in bile acid composition may modify calcium solubility or GB function, thereby contributing to the increased GB calcium observed during cholesterol and pigment gallstone formation.     

Hydrophilic bile acids: Prevention and dissolution experiments in two animal models of cholesterol cholelithiasis

The effects of β-muricholic acid and hyocholic acid on cholesterol cholelithiasis were examined in two animal models. The following experiments were carried out: A) In a gallstone prevention study, prairie dogs were fed the lithogenic diet with or without 0.1% β-muricholic or 0.1% hyocholic acid for eight weeks. B) In a second prevention study, hamsters were fed the lithogenic diet with or without 0.1% β-muricholic acid or 0.1% hyocholic acid for six weeks. C) In a gallstone dissolution study, hamsters were fed the lithogenic diet for six weeks to induce stones; stone dissolution was examined during administration of a cholesterol-free purified diet with or without 0.1% β-muricholic acid or 0.1% hyocholic acid. In the prevention study in prairie dogs (A), both bile acids failed to prevent stone formation, the cholesterol saturation index of bile was 0.89 in the lithogenic controls, remained unchanged with hyocholic acid and increased to 1.52 in the β-muricholic acid group. In the prevention study in hamsters (B), β-muricholic acid completely inhibited the cholesterol cholelithiasis (0% stone incidence); the cholesterol saturation index of bile was 1.78 (compared to lithogenic controls, 1.37). Hyocholic acid reduced stone incidence to 16% with a cholesterol saturation index of 0.98. In the dissolution study in hamsters (C), preexisting cholesterol gallstones were not dissolved by either hydrophilic bile acid after feeding these bile acids for an additional six weeks; at the end of the experiment, the cholesterol saturation indices were below unity. These studies suggest that, in the hamster animal model, hydrophilic bile acids may be useful for the prevention of gallstones but not dissolution of preestablished cholesterol gallstones.     

Differential effects of ursodeoxycholic acid and ursocholic acid on the formation of biliary cholesterol crystals in mice

The preventive effect of 3α,7β,12α-trihydroxy-5β-cholanoic acid (ursocholic acid) and ursodeoxycholic acid on the formation of biliary cholesterol crystals was studied in mice. Cholesterol crystals developed with 80% incidence after feeding for five weeks a lithogenic diet containing 0.5% cholesterol and 0.25% sodium cholate. When 0.25% ursocholic acid or ursodeoxycholic acid was added to the lithogenic diet, the incidence as well as the grade (severity) of the gallstones were reduced. Plasma and liver cholesterol levels were decreased by ursodeoxycholic acid but not by ursocholic acid. Gallbladder cholesterol and phospholipid levels were decreased by both bile acids. The biliary bile acid level was decreased by ursocholic acid but not by ursodeoxycholic acid. After feeding ursocholic acid, its level in the bile was about 25% and the levels of cholic acid and β-muricholic acid decreased. Fecal sterol excretion was not changed by ursocholic acid, but was increased by ursodeoxycholic acid. After feeding ursocholic acid, fecal excretion of deoxycholic acid, cholic acid, and ursocholic acid increased. No differences were found between mice, with or without gallstones, in plasma and liver cholesterol levels, biliary phospholipid and bile acid levels, fecal sterol and bile acid levels, and biliary and fecal bile acid composition. The results suggest that the lower incidence of crystal formation after treatment with ursocholic acid is probably by a different mechanism than with ursodeoxycholic acid. In the mouse model, ursodeoxycholic acid exerts its effect at least partially, by decreasing cholesterol absorption. Ursocholic acid is well absorbed and excreted into bile and transformed into deoxycholic acid by the intestinal microflora in mice.     

Effects of feeding chenodeoxycholic acid on metabolism of cholesterol and bile acids in germ-free rats

The aim of this investigation was to study the influence of chenodeoxycholic acid administration on cholesterol and bile acid synthesis in germ-free rats. Seven rats were fed a basal diet and 2 groups of 4 rats received the same diet supplemented with 0.4 and 1% chenodeoxycholic acid, respectively. After 6 weeks, feces were collected in one 3- and one 4-day pool for analysis of cholesterol and bile acids. When the sampling period was finished, the rats were killed and the liver microsomal fractions isolated. The activities of HMG CoA reductase and cholesterol 7α-hydroxylase were determined, the 7α-hydroxylase by a mass fragmentographic method. The 2 dominating bile acids in the untreated rats were cholic acid and β-muricholic acid. During treatment with chenodeoxycholic acid, 60–70% of this bile acid was converted into α- and β-muricholic acid, indicating a high activity of the 6β-hydroxylase. The excretion of cholic acid was almost completely inhibited and the 7α-hydroxylase activity was decreased ca 75% in the rats fed 1% chenodeoxycholic acid. The activity of the hepatic HMG CoA reductase was unchanged. The fecal excretion of cholesterol increased 2–3 times. An accumulation of cholesterol was seen in the rats treated with 1% chenodeoxycholic acid, which was probably a result of the decreased catabolism of cholesterol to bile acids.     

Effects of triton WR 1339 and orotic acid on lipid metabolism in rats

In order to investigate the effect of hepatic cholesterol flux on biliary bile acids, Triton WR 1339 and orotic acid were administered to rats, and the biliary cholesterol, phospholipids and bile acids were analyzed together with serum lipoproteins and hepatic lipids. Triton, which raised serum very low density lipoprotein and lipid levels and decreased serum high density lipoprotein liver lipid levels, increase the biliary cholic acid group/chenodeoxycholic acid group ratio (CA/CDCA) in the bile without affecting the total amount of bile acids and the other biliary lipids. Orotic acid, which decreased serum lipid and lipoprotein concentrations and increased liver lipid levels, increased the biliary excretion of cholesterol and phospholipids, but produced no significant change in the total amount of bile acids and in the CA/CDCA ratio in bile.     

Bile Acids Conjugation in Human Bile Is Not Random: New Insights from <Superscript>1</Superscript>H-NMR Spectroscopy at 800 MHz

Bile acids constitute a group of structurally closely related molecules and represent the most abundant constituents of human bile. Investigations of bile acids have garnered increased interest owing to their recently discovered additional biological functions including their role as signaling molecules that govern glucose, fat and energy metabolism. Recent NMR methodological developments have enabled single-step analysis of several highly abundant and common glycine- and taurine- conjugated bile acids, such as glycocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid. Investigation of these conjugated bile acids in human bile employing high field (800 MHz) ¹H-NMR spectroscopy reveals that the ratios between two glycine-conjugated bile acids and their taurine counterparts correlate positively (R ² = 0.83–0.97; p = 0.001 × 10⁻²–0.006 × 10⁻⁷) as do the ratios between a glycine-conjugated bile acid and its taurine counterpart (R ² = 0.92–0.95; p = 0.004 × 10⁻³–0.002 × 10⁻¹⁰). Using such correlations, concentration of individual bile acids in each sample could be predicted in good agreement with the experimentally determined values. These insights into the pattern of bile acid conjugation in human bile between glycine and taurine promise useful clues to the mechanism of bile acids’ biosynthesis, conjugation and enterohepatic circulation, and may improve our understanding of the role of individual conjugated bile acids in health and disease. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Effect of SMP-500, a novel ACAT inhibitor,on hepatic cholesterol disposition in rats

The effects of SMP-500, a novel ACAT inhibitor, on serum lipid levels, hepatic lipid secretion rate, and hepatic lipid disposition in rats were studied to clarify its lipid-lowering action. SMP-500 reduced the serum cholesterol level in a dose-dependent manner in rats fed a hypercholesterolemic diet. SMP-500 also reduced hepatic free cholesterol content in addition to hepatic total and esterified cholesterol contents. Biliary concentrations of cholesterol and bile acid were increased by SMP-500; however, the bile flow and lithogenic index were not affected. SMP-500 increased cholesterol 7α-hydroxylase mRNA level. Therefore, it is suggested that the increase in concentrations of cholesterol and bile acid in bile is due to both the increase of bile acid production through the increase of cholesterol 7α-hydroxylase and the decrease of hepatic free cholesterol content. An inhibitory effect of SMP-500 both on the cholesterol secretion and on the TG secretion from liver was observed. SMP-500 reduced the serum TG level in sucrose-fed rats. From these results, one may hypothesize that the suppression of hepatic VLDL secretion probably plays an important role on both cholesterol- and TG-lowering effects of SMP-500.     

Metabolism and cholestatic effect of 3α-hydroxy-7ζ-methyl-5β-cholanoic acid

3α-Hydroxy-7ζ-methyl-5β-cholanoic acid (7ζ-methyl-LA) was infused intravenously into bile fistula hamsters to investigate its metabolism and effect on the bile flow as compared with lithocholic acid. Following infusion of the labeled bile acids, bile was collected quantitatively to allow measurement of bile flow and bile acid composition. More than 80% of radioactivity was recovered in bile within 4 hr. 7ζ-Methyl-LA and lithocholic acid in bile were present as the taurine and glycine conjugates; no free bile acids were detected. 7ζ-Methyl-LA was neither hydroxylated nor metabolized to any measurable extent, though lithocholic acid was 7α-hydroxylated to chenodeoxycholic acid (30–45%). At the infusion rate at which lithocholic acid induced a severe cholestasis (264 nmol/min), 7ζ-methyl-LA did not decrease the bile flow. In fact, the infusion of 7ζ-methyl-LA produced a mild choleresis under conditions where endogenous bile acid excretion was not changed appreciably compared to control infusions with albumin. It is concluded that 7ζ-methyl-LA is not metabolized in the hamster but is conjugated with taurine and glycine, and that the introduction of a methyl group at the 7-position of lithocholic acid appears to alleviate the cholestatic effect of lithocholic acid in the hamster.     

Visualization of Bile Homeostasis Using <Superscript>1</Superscript>H-NMR Spectroscopy as a Route for Assessing Liver Cancer

Changes in bile synthesis by the liver or alterations in the enterohepatic circulation due to a variety of etiological conditions may represent a novel source of liver disease-specific biomarkers. Bile from patients with liver diseases exhibited significant changes in the levels of glycine- and taurine-conjugated bile acids, phospholipids, cholesterol and urea relative to non-liver disease controls. Cholangiocarcinoma and non-malignant liver diseases (NMLD) showed the most significant alterations. Further, hepatocellular carcinoma (HCC) could be differentiated from NMLD (p = 0.02), as well as non-liver disease controls (p = 0.02) based on the amounts of bile acids, phospholipids and/or cholesterol. HCC also differed with cholangiocarcinoma although not significantly. Urea increases somewhat in non-malignant liver disease relative to non-liver disease controls, while the bile acids, phospholipids and cholesterol all decrease significantly. The ratio between some major bile metabolites also distinguished NMLD (p = 0.004–0.01) from non-liver disease controls. This snapshot view of bile homeostasis, is obtainable from a simple nuclear magnetic resonance (NMR) approach and demonstrates the enormous opportunity to assess liver status, explore biomarkers for high risk diseases such as cancers and improve the understanding of normal and abnormal cellular functions.