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PubMed2000

Bile salt excretion in skate liver is mediated by a functional analog of Bsep/Spgp, the bile salt export pump.

Biliary secretion of bile salts in mammals is mediated in part by the liver-specific ATP-dependent canalicular membrane protein Bsep/Spgp, a member of the ATP-binding cassette superfamily. We examined whether a similar transport activity exists in the liver of the evolutionarily primitive marine fish Raja erinacea, the little skate, which synthesizes mainly sulfated bile alcohols rather than bile salts. Western blot analysis of skate liver plasma membranes using antiserum raised against rat liver Bsep/Spgp demonstrated a dominant protein band with an apparent molecular mass of 210 kDa, a size larger than that in rat liver canalicular membranes, approximately 160 kDa. Immunofluorescent localization with anti-Bsep/Spgp in isolated, polarized skate hepatocyte clusters revealed positive staining of the bile canaliculi, consistent with its selective apical localization in mammalian liver. Functional characterization of putative ATP-dependent canalicular bile salt transport activity was assessed in skate liver plasma membrane vesicles, with [(3)H]taurocholate as the substrate. [(3)H]taurocholate uptake into the vesicles was mediated by ATP-dependent and -independent mechanisms. The ATP-dependent component was saturable, with a Michaelis-Menten constant (K(m)) for taurocholate of 40+/-7 microM and a K(m) for ATP of 0.6+/-0.1 mM, and was competitively inhibited by scymnol sulfate (inhibition constant of 23 microM), the major bile salt in skate bile. ATP-dependent uptake of taurocholate into vesicles was inhibited by known substrates and inhibitors of Bsep/Spgp, including other bile salts and bile salt derivatives, but not by inhibitors of the multidrug resistance protein-1 or the canalicular multidrug resistance-associated protein, indicating a distinct transport mechanism. These findings provide functional and structural evidence for a Bsep/Spgp-like protein in the canalicular membrane of the skate liver. This transporter is expressed early in vertebrate evolution and transports both bile salts and bile alcohols.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Somatostatin reduces bile secretion and loss of bile constituents in patients with external biliary drainage.

The effect of 24-hours continuous somatostatin-14 infusion on the volume of the bile secretion and on the bile composition were studied in seven patients with malignant biliary obstruction who had transhepatic external biliary drainage. The bile acid composition was measured with high performance liquid chromatography (HPLC). Somatostatin infusion significantly reduced the daily bile loss from median 473 ml to 140 ml (41 per cent, p = 0.01) with a concomitant significant reduction in the daily molar loss of cholesterol, triglyceride, Na+, K+, Cl-, Ca+2 and Mg+2. The loss of chloride and sodium was reduced with median 50 mmol/day each (p = 0.01). The relative concentrations of the measured bile constituents did not change significantly, except for bile acids (p = 0.02): the concentration of glycochenodeoxycholic acid increased significantly (p = 0.04). The molar loss of taurocholic acid decreased significantly (p = 0.035), so the increased concentration of glycochenodeoxycholic acid resulted only in a marginally significant reduction in the total molar loss of bile aids (p = 0.051). Somatostatin is a potent inhibitor of bile secretion. The peptide may be used in severely bile depleted patients for reducing their serious electrolyte and acidity problems. Analysis of bile acid composition by HPLC is well suited for further investigations of the regulatory mechanisms of bile acid secretion.

Aged↗

PubMed1976

[Effect of ursodeoxycholic acid on bile secretion and bile components. Comparison with chenodeoxycholic acid and dehydrocholic acid].

Effects of some bile acids on the biliary flow, BSP output and composition (phospholipid, cholesterol, bilirubin and bile acids) were studied in dogs. Ursodeoxycholic acid (UD), chenodeoxycholic acid (CD) and dehydrocholic acid (DC) caused a dramatic increase in biliary flow and BSP output. Relative potencies of these effects were DC greater than CD greater than or equal to UD. UD increased the phospholipid, bile acids and cholesterol concentration but had little effect on bilirubin concentration. Furthermore, UD greatly increased the output of four bile components. CD slightly decreased the phospholipid, cholesterol and bilirubin concentration without the bile acids, while CD increased the output of bile components. After UD or CD administration, the bile acid of each appeared markedly in the bile, dose dependently. On the other hand, DC caused a dramatic decrease of phospholipid, cholesterol and bilirubin concentration but had little effect on bile acids concentration. Output of bile components was increased by DC the first 1 hr but decreased at 2 hr. After DC administration, 3alpha, 7alpha-dihydroxy-12keto-5beta-cholanic acid appeared in the bile while DC did not. Therefore, it is concluded that UD and CD are cholanereticas and DC is a hydrocholeretica.

Animals↗

PubMed1989

Role of bile acid conjugation in hepatic transport of dihydroxy bile acids.

The effect of conjugation and side chain length on dihydroxy bile acid unidirectional hepatic uptake and efflux was studied using the isolated perfused rat liver which was perfused prograde or retrograde in single pass fashion. Deoxycholic acid (DC) and its C23 (nor) derivative nor-DC, as well as the synthetically prepared taurine conjugate of DC, were administered at a constant dose of 1 mumol/min/kg (body weight), upon which a bolus tracer dose of labeled bile acid was superimposed. Analysis of radioactivity recovery in perfusate indicated that unidirectional uptake of all three bile acids was equally rapid, but that only nor-DC showed considerable and continuing efflux into the perfusate; this involved mostly the unchanged acid. Nor-DC was not amidated but was metabolized to mostly ester glucuronides and hydroxylated derivatives; the biotransformation products did not reflux and were secreted into bile; similarly, DC was amidated with taurine; its taurine conjugate did not efflux and was secreted into bile. When nor-DC-taurine was infused, it did not efflux and was secreted rapidly into bile. When the liver was perfused retrograde fashion to increase concentrations of bile acids pericentral cells, only nor-DC showed efflux, which again involved only the unchanged acid. All bile acids were partly 7 alpha-hydroxylated, the magnitude being greater during retrograde perfusion presumably because slower cellular transport exposed bile acid to hydroxylation enzymes for a longer period. It is concluded that bile acid conjugation, whether by esterification with CoA formation adn subsequent amidation or by esterification with glucuronate, restricts the movement of lipophilic dihydroxy bile acids to the hepatocyte and canalicular lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

A bile alcohol sulfate as a major component in the bile of the small skate (Raja erinacea).

The nature of bile alcohols and bile acids in gall-bladder and hepatic bile from perfused livers of the small skate (Raja erinacea) has been investigated. The main bile alcohol sulfate was isolated by thin-layer chromatography and analyzed by fast atom bombardment mass spectrometry and 13C NMR. Following solvolysis and purification on Lipidex-DEAP, the bile alcohol profile was measured by capillary gas-liquid chromatography-electron impact mass spectrometry. Based on these studies and on comparison with authentic scymmnol sulfate and scymnol, the main bile alcohol was identified as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,26,27-hexol sulfate. The mean +/- SD concentration in gallbladder bile from five different skates was 24.6 +/- 8.7 mmol/l. Only 0.1 mmol/l of cholic acid and its conjugates was found in a pool of skate bile. The main bile alcohol sulfate in the bile of the small skate seems to be a metabolic end product, present in a concentration comparable to that of bile salts in mammals.

Animals↗

PubMed1994

Bile acid transport by the rat liver canalicular bile acid transport/ecto-ATPase protein is dependent on ATP but not on its own ecto-ATPase activity.

We have shown that bile acid efflux and ecto-ATPase activities are two distinct properties of a single rat liver hepatocyte canalicular membrane protein (Sippel, C. J., Suchy, F. J., Ananthanarayanan, M., and Perlmutter, D. H. (1993) J. Biol. Chem. 268, 2083-2091). Bile acid efflux in COS cells transfected with this rat hepatocyte canalicular bile acid transport/ectoATPase cDNA is stimulated by ATP and inhibited by nonhydrolyzable ATP analogs. In this study, we depleted transfected COS cells of ATP to examine whether bile acid efflux mediated by this transporter was dependent on ATP or just stimulated by ATP. We also used mutagenesis of an ATPase consensus sequence in the ectoplasmic domain to examine the relationship of ATPase activity to bile acid efflux mediated by the same polypeptide. The results indicate that bile acid transport is abrogated by ATP depletion and reconstituted by exogenous ATP in a concentration-dependent and saturable manner. Introduction of mutations at amino acids Gly97 and Arg98 in the ATPase consensus sequence abrogated ATPase activity but did not affect synthesis or cell surface delivery of the transporter and did not affect its bile acid transport activity. Taken together, the data indicate that bile acid efflux mediated by the rat hepatocyte canalicular bile acid transport/ecto-ATPase protein is dependent on ATP but not on its own ATPase activity. The data, therefore, imply that 1) ATP affects its bile acid transport activity through an entirely distinct mechanism; and 2) if there is any functional relationship between the ecto-ATPase and bile acid transport properties, it is mediated indirectly through regulation of net ATP concentrations in the canalicular space by the ecto-ATPase.

Adenosine Triphosphatases↗

PubMed1977

Effect of ethynylestradiol on biliary excretion of bile acids, phosphatidylcolines, and cholesterol in the bile fistula rat.

The effects of ethynylestradiol on endogenous bile acids, their capacity to conjugate and excrete intravenously infused cholic acid, the concentrations of biliary cholesterol and lecithin, and the individual molecular species of phosphatidylcholine have been determined in male and female Sprague-Dawley rats. Endogenous biliary bile acids were analyzed by gas-liquid chromatography-mass spectrometry. Eleven bile acids were identified and several minor bile acids, primarily muricholates, could not be completely characterized. After 5 days of treatment with ethynylestradiol (1 mg/kg per day), the percentage of cholic acid decreased and the percentage of 6beta-hydroxylated bile acids, including several monounsaturated species, increased. Ethynylestradiol caused a decrease in bile acid-independent bile flow. Intravenous infusion of cholic acid at a high concentration caused cholestasis in control animals but, after ethynylestradiol treatment, cholestasis developed during the infusion of a much lower concentration of cholate, indicating a lowered threshhold for bile acid-induced cholestasis. In the treated rats, there was a slight increase in excretion of unconjugated endogenous bile acids, and a striking impairment of conjugation of intravenously administered cholic acid. One of the few sex-related differences observed was an increased concentration of biliary phospholipids in untreated male rats. Both phospholipid and cholesterol concentrations in the bile were higher in the treated animals. The molar percentage of cholesterol was always 1-2%, but it was slightly higher in treated animals, especially males. Ethynylestradiol treatment also affected biliary phospholipid by causing a marked increase of phosphatidylcholine species containing palmitic and oleic acid residues and a decrease of species containing stearic and linoleic acid residues. There was no increase in biliary excretion of long chain polyunsaturated species, which might have indicated damage to membranes, in response to ethynylestradiol either alone or with cholic acid infusion. Some of these ethynylestradiol-induced changes in biliary bile acid and lipid excretion are probably peculiar to the rat, but others, such as the increase in molar percentage of cholesterol and cholestasis, may be relevant to disorders in man, especially cholesterol gallstones and idiopathic cholestasis of pregnancy.

Animals↗

PubMed1996

The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia.

Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. The effects of these multiple factors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic role in liver disease it was intended to evaluate the effects of two principal therapeutic prostanoids, prostaglandin E2 and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin-induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E2 and prostacyclin was evaluated and compared to the response produced by bile salt infusion alone and to that produced by the standard choleretic hormones, secretin and glucagon. The animals were then fed alpha-naphthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatoxin that produces bile duct cell hyperplasia which was confirmed in dogs by demonstrating that ANIT increased [3H]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, secretin, and glucagon increased hepatic bile flow. 10 days of ANIT feeding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prostaglandin E2, prostacyclin, or glucagon appeared to stimulate the hyperplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potential therapeutic role in increasing bile flow in cholestatic liver disorders associated with bile duct cell hyperplasia.

1-Naphthylisothiocyanate↗

PubMedDate not supplied

Bile acid metabolism in cirrhosis. VII. Evidence for defective feedback control of bile acid synthesis.

The present report has been directed toward providing additional information on the major defects in the bile acid pathways present in patients with cirrhosis and its relevance to the problem of how bile acid synthesis is regulated in man. An unusual patient with severe liver disease and a completely broken enterohepatic circuit was studied. The synthesis of cholic and chenodeoxycholic acids was examined over a 5-d period. The secretion rats and the incorporation of [3H]7 alpha-hydroxycholesterol and [3H]26-hydroxycholesterol into both primary bile acids in the cirrhotic bile fistula patient was cross compared to earlier data obtained on patients with and without liver disease and an intact enterohepatic circuit and patients with no liver disease and a bile fistula. The daily synthesis rate of cholic acid increased 7-fold and chenodeoxycholic acid 2-fold in the cirrhotic bile fistula patient. The incorporation of [3H]7 alpha- hydroxycholesterol into bile acids in the cirrhotic bile fistula patient was efficient (75%) and equal to bile fistula patients with no cirrhosis (76%); chenodeoxycholic acid synthesis was favored over cholic acid particularly in the cirrhotic patient. [3H]26-hydroxycholesterol was poorly incorporated in patients with no cirrhosis (25%) and the cirrhotic patient (20%); chenodeoxycholic acid was favored by a wide margin. It is concluded from this and previous reports that the profound reduction in bile acid synthesis present in patients with cirrhosis is not caused singly by a failure in the metabolic pathways from 7 alpha-hydroxycholesterol to cholic and chenodeoxycholic acid (i.e., 12 alpha-hydroxylation step), but rather due to a defect in the feedback control regulating bile acid synthesis.

Bile Acids and Salts↗

PubMedDate not supplied

Bile acid metabolism in cirrhosis. VIII. Quantitative evaluation of bile acid synthesis from [7 beta-3H]7 alpha-hydroxycholesterol and [G-3H]26-hydroxycholesterol.

In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [3H]7 alpha-hydroxycholesterol and [3H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [14C]cholic and [14C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs. 927 mumoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 mumoles per day). The administration of [3H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [3H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and /or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway.

Adult↗

PubMed1994

Fetal bile acid metabolism during infancy: analysis of 1 beta-hydroxylated bile acids in urine, meconium and feces.

Fetal bile acids (1 beta-hydroxylated, 6 alpha-hydroxylated and unsaturated bile acids), especially 1 beta, 3 alpha,7 alpha, 12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid (CA-1 beta-ol), have been detected in urine and feces early in life. To investigate whether a fetal pathway of bile acid synthesis exists in infancy, we measured the concentrations of bile acids in the urine, meconium and feces from normal newborns and infants by means of gas chromatography-mass spectrometry. The mean ratio of total bile acids to creatinine in urine increased between birth and 7 days and then gradually decreased; however, the concentration of total bile acids in urine remained significantly higher than that in adult urine until 3 mo of age. The main urinary bile acid was CA-1 beta-ol, and substantial amounts of fetal bile acids were detected in urine until 3 mo of age. The ratio of cholic acid to chenodeoxycholic acid was abnormally low in meconium (mean, 0.44; range, 0.19 to 0.74), and hyocholic acid constituted 19.3% of total bile acids. The mean total bile acid content of feces decreased between birth and 7 days of age and thereafter increased. The mean percentage of fetal bile acids in feces decreased after birth, but substantial amounts were present in feces until 1 mo of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1996

Enzymatic determination of serum 3 alpha-sulfated bile acids concentration with bile acid 3 alpha-sulfate sulfohydrolase.

A newly developed enzymatic method for determining urinary 3 alpha-sulfated bile acids was used to measure serum 3 alpha-sulfated bile acid levels in 114 patients with hepatobiliary diseases and 56 healthy subjects. The lowest measurable amount of the 3 alpha-sulfated bile acids was 0.5 mumol/liter. The standard curves for glycolithocholic acid 3 alpha-sulfate, glycoursodeoxycholic acid 3 alpha-sulfate, and lithocholic acid 3 alpha-sulfate were linear from 0.5 to 250 mumol/liter. Specificity of the assay was satisfactory and intra- and interassay variations ranged from 0.8 to 4.4% and from 1.2 to 7.9%, respectively. Analytical recovery was more than 91%. The values obtained by this assay were well correlated with those by gas-liquid chromatography measurement (r = 0.91, P < 0.01). The fasting serum 3 alpha-sulfated bile acids level in healthy subjects ranged from undetectable to 1.9 mumol/liter (mean +/- SE; 0.9 +/- 0.1 mumol/liter). The percentage of 3 alpha-sulfated bile acids in total bile acids (sum of 3 alpha-sulfated and 3 alpha-hydroxy bile acids) in serum was 16.8 +/- 1.5%. In subjects with hepatobiliary diseases, serum 3 alpha-sulfated bile acids levels were elevated; however, the percentage of 3 alpha-sulfated bile acids in total bile acids was decreased and correlated with the severity of hepatocellular insufficiency. This enzymatic assay is simple, rapid, and accurate for the determination of serum 3 alpha-sulfated bile acids.

Adult↗

PubMed1988

Maintenance of hepatic bile acid secretion rate during overnight fasting by bedtime bile acid administration.

We have tested the hypothesis that the greater clinical efficacy of bedtime administration of bile acid in gallstone dissolution is due to prevention of the reduction in hepatic bile acid secretion that normally accompanies overnight interruption of the enterohepatic circulation, thus also reducing the secretion of supersaturated hepatic bile. We measured the hepatic bile acid secretion rate by combining duodenal perfusion of a nonabsorbable recovery marker (polyethylene glycol) with continuous intravenous infusion of a hepatic bile marker (indocyanine green). We studied 6 subjects with gallstones before and during administration of ursodeoxycholic acid (UDCA, 675 mg) at bedtime. Duplicate pretreatment studies revealed good reproducibility. Mean values for hepatic bile acid secretion rate were uninfluenced by chronic UDCA administration before the acute bedtime dose, but during the 4-h period after acute administration of UDCA the total bile acids secreted increased by a mean value of 2.2 mmol (p less than 0.01). Before treatment, nine of the 78 hourly samples were secreted at a hepatic bile acid secretion rate of less than 5 mumol/kg.h in the 6 patients studied, compared with only one hourly sample during UDCA administration. Super-saturated hepatic bile was secreted for a mean of 9.5 h before treatment, and for 1.2 h during UDCA treatment (p less than 0.005). We conclude that if UDCA is administered at bedtime, this maintains the hepatic bile acid secretion rate overnight, thus reducing secretion of supersaturated hepatic bile, in addition to the well-established effect of UDCA on cholesterol secretion.

Aged↗

PubMed2002

Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice.

BACKGROUND/AIMS: Expression of hepatic bile salt transporters is partly regulated by bile salts via activation of nuclear farnesoid X-activated receptor (Fxr). We investigated the physiological relevance of this regulation by evaluating transporter expression in mice experiencing different transhepatic bile salt fluxes. METHODS: Bile salt flux was manipulated by dietary supplementation with taurocholate (0.5% w/w) or cholestyramine (2% w/w) or by disruption of the cholesterol 7alpha-hydroxylase-gene (Cyp7A(-/-) mice) leading to reduced bile salt pool size. Expression of hepatic transporters was assessed (polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry). RESULTS: Biliary bile salt secretion was increased (+350%) or decreased (-50%) after taurocholate or cholestyramine feeding, respectively, but plasma bile salt concentrations and hepatic Fxr expression were not affected. The bile salt uptake system Na(+)-taurocholate co-transporting polypeptide (Ntcp) and organic anion transporting polypeptide-1 (Oatp1) were down-regulated by taurocholate and not affected by cholestyramine feeding. Cyp7A(-/-) mice did not show altered Ntcp or Oatp1 expression. Canalicular bile salt export pump (Bsep) was up-regulated by 65% in taurocholate-fed mice, and slightly down-regulated in Cyp7A(-/-) mice. CONCLUSIONS: Large variations in hepatic bile salt flux have minor effects on expression of murine Ntcp and Bsep in vivo, suggesting that these transporters are abundantly expressed and able to accommodate a wide range of 'physiological' bile salt fluxes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Transbilayer movement of fully ionized taurine-conjugated bile salts depends upon bile salt concentration, hydrophobicity, and membrane cholesterol content.

Taurine-conjugated bile salts mediate rapid transmembrane flux of divalent cations, irrespective of whether bile salts and divalent cations are initially on the same or opposite side of the membrane. We therefore hypothesized that ionized bile salts can equilibrate between membrane hemileaflets. We quantitated bile salt binding to large unilamellar egg yolk phosphatidylcholine (EYPC) +/- cholesterol (Ch) vesicles under conditions in which one or both hemileaflets were initially exposed to bile salts. At unbound taurodeoxycholate (TDC) concentrations >0.2 mM, the dependence of binding on TDC concentration after 30 min was indistinguishable for vesicles prepared by either method and did not change from 30 minutes to 24 h. At unbound TDC concentrations <0.1 mM, the ratio of bound/free TDC to EYPC vesicles doubled over a single exponential time course. Equilibration times were greater for the more hydrophilic bile salts taurocholate and tauroursodeoxycholate, for EYPC/Ch vesicles, and at lower temperatures. For glycine-conjugated bile salts, time-dependent changes in binding did not occur, consistent with more rapid equilibration of the small fraction of the protonated form. We conclude that fully ionized conjugated bile salts translocate between lipid bilayer hemileaflets, in contrast to previous observations that equilibration of fully ionized unconjugated bile salts occurs at a negligible rate in small unilamellar vesicles. The rate of "flip-flop" increases with increases in intramembrane bile salt concentration and hydrophobicity but decreases with cholesterol content and lower temperature. We speculate that physiologically, even in the absence of a specific membrane transporter, bile salts can gain access to intracellular compartments and mediate increases in divalent cation flux that may underlie cytotoxicity.

Bile Acids and Salts↗

PubMed2003

Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice.

The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids. In patients with primary bile acid malabsorption, mutations in the ileal bile acid transporter gene (Slc10a2) lead to congenital diarrhea, steatorrhea, and reduced plasma cholesterol levels. To elucidate the quantitative role of Slc10a2 in intestinal bile acid absorption, the Slc10a2 gene was disrupted by homologous recombination in mice. Animals heterozygous (Slc10a2+/-) and homozygous (Slc10a2-/-) for this mutation were physically indistinguishable from wild type mice. In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin. Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice. On a low fat diet, the Slc10a2-/- mice did not have steatorrhea. Fecal neutral sterol excretion was increased only 3-fold, and intestinal cholesterol absorption was reduced only 20%, indicating that the smaller cholic acid-enriched bile acid pool was sufficient to facilitate intestinal lipid absorption. Liver cholesteryl ester content was reduced by 50% in Slc10a2-/- mice, and unexpectedly plasma high density lipoprotein cholesterol levels were slightly elevated. These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function.

Alleles↗

PubMed2005

Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids.

The fibroblast growth factor (FGF) receptor complex is a regulator of adult organ homeostasis in addition to its central role in embryonic development and wound healing. FGF receptor 4 (FGFR4) is the sole FGFR receptor kinase that is significantly expressed in mature hepatocytes. Previously, we showed that mice lacking mouse FGFR4 (mR4(-/-)) exhibited elevated fecal bile acids, bile acid pool size, and expression of liver cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for canonical neutral bile acid synthesis. To prove that hepatocyte FGFR4 was a negative regulator of cholesterol metabolism and bile acid synthesis independent of background, we generated transgenic mice overexpressing a constitutively active human FGFR4 (CahR4) in hepatocytes and crossed them with the FGFR4-deficient mice to generate CahR4/mR4(-/-) mice. In mice expressing active FGFR4 in liver, fecal bile acid excretion was 64%, bile acid pool size was 47%, and Cyp7a1 expression was 10-30% of wild-type mice. The repressed level of Cyp7a1 expression was resistant to induction by a high cholesterol diet relative to wild-type mice. Expression of CahR4 in mR4(-/-) mouse livers depressed bile acid synthesis below wild-type levels from the elevated levels observed in mR4(-/-). Levels of phosphorylated c-Jun N-terminal kinase (JNK), which is part of a pathway implicated in bile acid-mediated repression of synthesis, was 30% of wild-type levels in mR4(-/-) livers, whereas CahR4 livers exhibited an average 2-fold increase. However, cholate still strongly induced phospho-JNK in mR4(-/-) livers. These results confirm that hepatocyte FGFR4 regulates bile acid synthesis by repression of Cyp7a1 expression. Hepatocyte FGFR4 may contribute to the repression of bile acid synthesis through JNK signaling but is not required for activation of JNK signaling by bile acids.

Animals↗

PubMed1999

Increased fecal bile acid excretion and changes in the circulating bile acid pool are involved in the hypocholesterolemic and gallstone-preventive actions of psyllium in hamsters.

The lipid-lowering effect of psyllium (PSY) is well established. Enhanced fecal bile acid excretion and a stimulation of hepatic bile acid synthesis are discussed as primary mechanisms of this action. To further examine the effect of bile acid excretion and specifically of compositional alterations in the bile acid pool on the cholesterol-lowering and gallstone-preventing action of PSY, male golden Syrian hamsters were fed lithogenic diets containing 5 g/100 g fat, 0.4 g/100 g cholesterol and 0 (control), 4 or 6% PSY or 1% cholestyramine (CHY). PSY significantly lowered plasma total cholesterol and triacylglycerol at a magnitude comparable to that induced by CHY. Although hepatic cholesteryl ester accumulation was completely inhibited by CHY, PSY did not prevent the hepatic storage of esterified cholesterol. PSY and CHY caused distinct alterations in the bile acid profile. PSY caused a selective reduction of taurine-conjugated bile acids, especially of taurochenodeoxycholate. As a result, the glycine:taurine conjugation and the cholate:chenodeoxycholate ratios were significantly higher in PSY-fed hamsters. PSY and CHY normalized the lithogenic index and prevented cholesterol gallstone formation compared with controls. Daily fecal bile acid excretion was approximately 400% greater in hamsters fed 6% PSY, whereas CHY caused an 11-fold increase. Daily neutral sterol excretion did not differ in PSY-fed hamsters but was >100% greater in those fed CHY than in controls. These data emphasize the potent lipid-lowering effect of PSY. Increased fecal bile acid excretion and alterations of the circulating bile acid pool by removal of dihydroxy bile acids (e.g., taurochenodeoxycholate) appear to be main modulators of the hypocholesterolemic action of PSY by leading to an up-regulation of hepatic bile acid synthesis.

Analysis of Variance↗