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PubMed2005

1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media.

The unconjugated bile acids cholic acid, deoxycholic acid, and chenodeoxycholic acid; their glycine and taurine conjugates glycocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid; and a taurine conjugated ursodeoxycholic acid, tauroursodeoxycholic acid, were characterized through 1H and 13C NMR in aqueous media under the physiological pH region (7.4 +/- 0.1). Assignments of 1H and 13C signals of all the bile acids were made using a combination of several one- and two-dimensional, homonuclear (1H-1H) and heteronuclear (1H-13C) correlations as well as spectral editing NMR methods. Stereochemical assignment of the five-membered ring of the bile acids is reported here for the first time. The complete characterization of various bile acids in aqueous media presented here may have implications in the study of the pathophysiology of biliary diseases through human biliary fluids using NMR spectroscopy.

Bile Acids and Salts↗

PubMed1993

Micellar electrokinetic capillary chromatography analysis of the behavior of bilirubin in micellar solutions.

The capacity factor of bilirubin is determined by micellar electrokinetic capillary chromatography (MECC) techniques in three different surfactant systems. The capacity factor of bilirubin in cholic acid, taurocholic acid, and taurochenodeoxycholic acid solutions are compared to each other as a function of pH. The pH range studied is 6.5 to 9.5 which includes the pH range of bile, and includes the most likely pKa values of bilirubin carboxyl groups. MECC techniques are used to estimate these apparent pKa values for bilirubin as well as to determine the capacity factors for the separate ionization states of bilirubin in the three different surfactants. Due to the complexity of the bilirubin-bile salt system, it appears as though it is not possible to use MECC to accurately determine the bilirubin apparent pKa values. Separations are performed in 75 microns capillaries, typically 36 to 52 cm in length. UV detection, electrokinetic injection, and run voltages of 7 kV are typical. Solutions of 25 mM of each bile salt are prepared in a 20 mM phosphate-borate buffer system.

Bilirubin↗

PubMed1995

Enzymatic characterization of a novel bovine liver dihydrodiol dehydrogenase--reaction mechanism and bile acid dehydrogenase activity.

Bovine liver cytosolic dihydrodiol dehydrogenase (DD3) has been characterized by its unique dihydrodiol dehydrogenase activity for trans-benzenedihydrodiol (trans-1,2-dihydrobenzene-1,2-diol) with the highest affinity and the greatest velocity among three multiple forms of dihydrodiol dehydrogenases (DD1-DD3). It is the first time that DD3 has shown a significant dehydrogenase activity for (S)-(+)-1-indanol with low Km value (0.33 +/- 0.022 mM) and high K(cat) value (25 +/- 0.79 min-1). The investigation of the product inhibition of (S)-(+)-1-indanol with NADP+ versus 1-indanone and NADPH clearly showed that the enzymatic reaction of DD3 may follow a typical ordered Bi Bi mechanism similar to many aldo/keto reductases. Additionally, DD3 was shown to catalyze the dehydrogenation of bile acids (lithocholic acid, taurolithocholic acid and taurochenodeoxycholic acid) having no 12-hydroxy groups with low Km values (17 +/- 0.65, 33 +/- 1.9 and 890 +/- 73 microM, respectively). In contrast, DD1, 3 alpha-hydroxysteroid dehydrogenase, shows a broad substrate specificity for many bile acids with higher affinity than those of DD3. Competitive inhibition of DD3 with androsterone against dehydrogenase activity for (S)-(+)-1-indanol, trans-benzenedihydrodiol or lithocholic acid suggests that these three substrates bind to the same substrate binding site of DD3, different from the case of human liver bile acid binder/dihydrodiol dehydrogenase (Takikawa, H., Stolz, A., Sugiyama, Y., Yoshida, H., Yamamoto, M. and Kaplowitz, N. (1990) J. Biol. Chem. 265, 2132-2136). Considering the reaction mechanism, DD3 may also play an important role in bile acids metabolism as well as the detoxication of aromatic hydrocarbons.

Animals↗

PubMed2002

Regulation of oxysterol 7alpha-hydroxylase (CYP7B1) in primary cultures of rat hepatocytes.

Conversion of cholesterol into 7alpha-hydroxylated bile acids is a principal pathway of cholesterol disposal. Cholesterol 7alpha-hydroxylase (CYP7A1) is the initial and rate-determining enzyme in the "classic" pathway of bile acid synthesis. An "alternative" pathway of bile acid synthesis is initiated by sterol 27-hydroxylase (CYP27) with subsequent 7alpha-hydroxylation of 27-hydroxycholesterol by oxysterol 7alpha-hydroxylase (CYP7B1). The regulation of CYP7B1, possibly a rate-determining enzyme in the alternative pathway, has not been thoroughly studied. The aims of this study were to (1) study the regulation of liver CYP7B1 by bile acids, cholesterol, adenosine 3', 5'-cyclic monophosphate (cAMP), and phorbol myristate acetate (PMA) in primary rat hepatocytes and (2) determine the effect of CYP7B1 overexpression on rates of bile acid synthesis. The effects of different bile acids (3-150 micromol/L), cAMP (50 micromol/L), PMA (100 nmol/L; protein kinase C stimulator), cholesterol (200 micromol/L), and squalestatin (1 micromol/L; cholesterol synthesis inhibitor) on CYP7B1 expression in primary rat hepatocytes were studied. Taurocholic acid and taurodeoxycholic acid decreased CYP7B1 activity by 45% +/- 10% and 36% +/- 7%, respectively. Tauroursodeoxycholic acid and taurochenodeoxycholic acid did not alter CYP7B1 activity. Inhibition of cholesterol synthesis with squalestatin decreased CYP7B1 activity by 35%, whereas addition of cholesterol increased activity by 39%. Both PMA and cAMP decreased CYP7B1 activity by 60% and 34%, respectively, in a time-dependent fashion. Changes in CYP7B1 messenger RNA (mRNA) levels correlated with changes in specific activities. Overexpression of CYP7B1 led to a marked increase in CYP7B1 mRNA levels and specific activity but no change in rates of bile acid synthesis. In conclusion, in the rat, CYP7B1 specific activity is highly regulated but does not seem to be rate limiting for bile acid synthesis.

Animals↗

PubMed2002

Differences in the regulation of the classical and the alternative pathway for bile acid synthesis in human liver. No coordinate regulation of CYP7A1 and CYP27A1.

It has been reported that there is a coordinate regulation of sterol 27-hydroxylase (CYP27A1) and cholesterol 7alpha-hydroxylase (CYP7A1) in rats. Thus, the levels of the mRNA corresponding to these two enzymes were found to change in the same direction in rat liver and in isolated rat hepatocytes. In contrast, other groups have not seen such regulation of CYP27A1 in rabbit liver or in rat liver when using an activity assay. In the present work, the effect of bile acid treatment on human CYP27A1/luciferase reporter activity was studied in a transient transfection assay in human liver-derived HepG2 cells. Neither the endogenous 27-hydroxylase activity nor the CYP27A1/luciferase reporter activity were down-regulated by treatment of HepG2 cells with chenodeoxycholic acid or taurochenodeoxycholic acid. We also measured CYP27A1 mRNA and CYP7A1 mRNA in liver of humans subjected to treatment with chenodeoxycholic acid, ursodeoxycholic acid, hydroxymethylglutaryl (HMG)-CoA reductase inhibitor and a combination of HMG-CoA reductase inhibitor and cholestyramine. There was a 60-fold variation in the levels of CYP7A1 mRNA but only a 5-fold variation in the levels of CYP27A1 mRNA. There was no correlation between the two mRNA species. It is concluded that, in humans, there is little or no coordinate regulation of CYP7A1 and CYP27A1 at the transcriptional level, and that CYP27A1 is not subject to a negative feedback control by bile acids. The results underline that marked species differences may exist in mechanisms for control of synthesis of bile acids and cholesterol homeostasis.

Bile Acids and Salts↗

PubMed1973

Effect of conjugated dihydroxy bile salts on electrolyte transport in rat colon.

The mechanism by which excess quantities of bile salts in the colon produce diarrhea is not known. Therefore, experiments were performed in which the effect of conjugated dihydroxy bile salts on ion transport was evaluated in the in vitro short-circuited rat colon. 2 mM glycochenodeoxycholic acid (GCDC), taurochenodeoxycholic acid (TCDC), or taurodeoxycholic acid caused a prompt increase in short-circuit current (I(sc)) and electrical potential difference (PD). Similar results were obtained when theophylline was added. Removal of HCO(2) and C1 prevented the effects of both bile salts and theophylline. Pretreatment with theophylline blocked the increase in I(sc) and PD produced by TCDC and pretreatment with either TCDC or GCDC inhibited the expected theophylline response. Na fluxes in the presence of both TCDC and theophylline demonstrated a decrease in net absorption; and TCDC decreased net C1 absorption and theophylline caused a reversal of net C1 absorption to net C1 secretion. It is proposed that the diarrhea associated with cholerheic enteropathy is produced by active anion secretion possibly mediated by cyclic AMP.

Animals↗

PubMed2003

Efficacy of a larger version of the hybrid artificial liver support system using a polyurethane foam/spheroid packed-bed module in a warm ischemic liver failure pig model for preclinical experiments.

We have reported the usefulness of a polyurethane foam packed-bed culture system of hepatocyte spheroids as a hybrid artificial liver support system (PUF-HALSS). The aim of this study was to evaluate in detail the efficacy in serum parameters regarding the liver function of a larger version of the PUF-HALSS containing 2 x 10(10) porcine hepatocytes for clinical use in warm ischemic liver failure pigs. Warm ischemic liver failure pigs weighing 25 kg were divided into two groups: (1) a control group (n = 3), in which each pig was attached to a PUF-HALSS without hepatocytes, and (2) a HALSS group (n = 3), in which each pig was attached to a PUF-HALSS. In the HALSS group, the increase of blood ammonia was completely suppressed and blood lactate levels were significantly suppressed. The Fisher's ratio was better maintained, and the increase of total bile acid, glycochenodeoxycholic acid, and taurochenodeoxycholic acid was significantly suppressed in the HALSS group. Serum creatinine levels were significantly lower, and blood glucose levels were significantly higher in the HALSS group. Serum levels of tumor necrosis factor- a were not elevated in either group. In conclusion, the larger version of the PUF-HALSS demonstrated many advantages as a liver support system in warm ischemic liver failure pigs.

Amino Acids↗

PubMed1990

Difference in enzymatic sulfation of bile acids between the mouse and rat.

Species difference in bile acid-sulfotransferase (BAST) activity was studied between the mouse and rat. Cytosol fractions of the liver, kidney, small intestine and large intestine were incubated with bile acids and 3' phosphoadenosine-5'-phosphosulfate. The mouse liver showed BAST activity for lithocholic acid, taurolithocholic acid and taurochenodeoxycholic acid, whereas the rat liver and kidney had the activity for taurodeoxycholic acid in addition to these compounds. The highest activities were found in the mouse liver and rat kidney. The mouse small intestine showed weak activity only for lithocholic acid. No activity was found in other organs. BAST was inactive towards taurocholic acid, 7 alpha- or 12-monohydroxy-5 beta-cholanoic acid. Optimal pH of liver BAST in the two species was different from that of the rat kidney. BAST of the mouse liver showed the highest activity without addition of Mg2+, whereas that of the rat liver and kidney showed enhancement by exogenous Mg2+. These results indicated that the distribution and characteristics of mouse BAST was different from rat BAST. Such difference should be reminded in any animal study involving the two species.

Animals↗

PubMed1995

Mechanism of ketoconazole-induced elevation of individual serum bile acids in the rat: relationship to the effect of ketoconazole on bile acid uptake by isolated hepatocytes.

Ketoconazole, an imidazole derivative, has been implicated in a number of hepatic dysfunctions. The aim of the present study was to determine the effect of in vivo treatment of rats with ketoconazole on individual serum bile acid levels and the in vitro effects of ketoconazole on the hepatocellular uptake of two bile acids and two other model substrates transported by liver cells. Male Sprague-Dawley rats were treated i.p. with a single injection of ketoconazole of 25 mg/kg (n = 4) or 50 mg/kg (n = 4); the control group (n = 4) received the vehicle only at a dose of 1 ml/kg. Blood samples were collected at 4 hr after dosing. With high-performance liquid chromatography, the serum was assayed for individual serum bile acids. At the higher dose, ketoconazole produced a significant increase in serum levels of cholic acid, taurocholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and taurochenodeoxycholic acid compared with the control group (P < .05). Cholic acid, taurocholic acid and chenodeoxycholic acid levels were significantly raised in rats treated with the lower dose. In vitro, ketoconazole strongly inhibited the hepatocellular uptake of [14C]cholic acid, [14C]taurocholic acid and [3H]ouabain but not [14C]2-aminoisobutyric acid, which indicated that the effect is relatively specific. The kinetics of inhibition were competitive and the inhibition constants for taurocholate and ouabain were 6 and 1 microM, respectively. Ketoconazole inhibited by both Na(+)-dependent taurocholate uptake and stimulated bile acid countertransport of preloaded hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1976

Bile acid structure and biliary secretion of cholesterol and phospholipid in the cat.

The effect of bile acid structure on biliary lipid composition was studied on the anesthetized bile fistula cat. The sodium salts of taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid were infused intravenously in 6 animals in random order in a Latin square design. Bile acids were infused for 2 hr at approximately 270 mumoles per hr; each bile acid period was preceded by a 1-hr infusion of isotonic NaCl. Bile samples from the 2nd hr of bile acid infusion, a period of steady bile acid secretion, were compared, and their bile acid, cholesterol, and phospholipid contents were measured. Mean bile acid secretion rates did not differ among the three bile acids, nor did mean phospholipd secretion rates. In contrast, cholesterol secretion was 3 to 4 times greater with the dihydroxy bile acids than with the trihydroxy bile acid, taurocholic acid. It is concluded that bile acid structure is an important determinant of the lipid composition of bile. Further, this comparison of bile acids has dissociated cholesterol from phospholipid secretion, suggesting that bile acids may influence cholesterol and phospholipid secretion independently.

Animals↗

PubMed1975

Bile salt alteration of ion transport across jejunal mucosa.

The effect of conjugated dihydroxy and trihydroxy bile salts on electrolyte transport across isolated rabbit jejunal mucosa was studied. Both taurochenodeoxycholic acid and taurocholic acid increased the short-circuit current (Isc) in bicarbonate-Ringer solution but not in a bicarbonate-free, chloride-free solution. Taurochenodeoxycholic acid was significantly more effective than taurocholic acid in increasing Isc. The presence of theophylline prevented the taurochenodeoxycholic acid- and taurocholic acid-induced increase in Isc. Transmural ion fluxes across jejunal mucosa demonstrated that 2 mM taurochenodeoxycholic acid decreased net Na+ absorption, increased net Cl- secretion and increased the residual flux (which probably represents HCO3- secretion). These studies support the hypothesis that cyclic AMP may be a mediator of intestinal electrolyte secretion.

Animals↗

PubMed1983

The metabolism of chenodeoxycholic acid to beta-muricholic acid in rat liver.

1. The synthesis of conjugated chenodeoxycholic acid and tauro-beta-muricholic acid in isolated rat hepatocytes was measured by radioimmunoassay. Production of tauro-beta-muricholic acid was linear over 4 h of incubation at 37 degrees C. The net synthesis of conjugated chenodeoxycholic acid was very much lower than that of tauro-beta-muricholic acid. 2. When hepatocytes were prepared from rats in which the enterohepatic circulation had been broken, either by feeding the bile salt sequestrant, cholestyramine or by total biliary drainage for 48 h, synthesis of tauro-beta-muricholic acid was increased compared to that in cells from control rats. Conjugated chenodeoxycholic acid accumulation during incubation of the hepatocytes was increased by cholestyramine feeding but not by total biliary drainage. These results suggest that there is a metabolic difference between the two methods of breaking the enterohepatic circulation with regard to chenodeoxycholic acid synthesis. 3. Hepatocytes prepared from rats given 1% cholesterol in the diet for at least 2 weeks synthesised significantly more tauro-beta-muricholic acid than those from control rats. The total amount of conjugated cholic, chenodeoxycholic and tauro-beta-muricholic acids synthesised by cells from cholesterol fed animals, however was not significantly different from that produced by hepatocytes from normal rats. 4. Exogenous taurochenodeoxycholic acid was metabolised to tauromuricholic acid by isolated hepatocytes. Production of tauro-beta-muricholic acid reached a maximum at a concentration of 20 microM taurochenodeoxycholic acid. The total metabolism of taurochenodeoxycholic acid, however, increased linearly up to the highest concentration measured, 50 microM. 5. The biliary content of tauro-beta-muricholic acid during total biliary drainage fell rapidly in the first 10 h and thereafter continued to decline, reaching a minimum after about 24 h. No significant rise was observed during the remainder of the experimental period. 6. It is concluded that a large proportion of the conjugated chenodeoxycholic acid synthesised by isolated hepatocytes in vitro is metabolised to tauro-beta-muricholic acid, and therefore it is necessary to take this into account when using this system to study bile salt synthesis.

Animals↗

PubMed2000

Competition in liver transport between chenodeoxycholic acid and ursodeoxycholic acid as a mechanism for ursodeoxycholic acid and its amidates' protection of liver damage induced by chenodeoxycholic acid.

BACKGROUND: Ursodeoxycholic acid has been widely used as a therapeutic agent in cholesterol gallstones and liver disease patients, but its mechanism of action is still under investigation. AIMS: The protective effect of ursodeoxycholic acid, both free, taurine and glycine conjugated, against hepatotoxic bile acids such as chenodeoxycholic acid and its taurine amidate was studied in bile fistula rats and compared with the cholic and taurocholic acid effect. METHODS: Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid, taurocholic acid and cholic acid were infused iv over 1 hour (8 micromol/min/kg) together with an equimolar dose of either taurochenodeoxycholic acid or chenodeoxycholc acid. Bile flow, total and individual bile acid and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. RESULTS: Taurochenodeoxycholic acid and chenodeoxycholc acid caused cholestasis and liver damage associated with a decreased bile flow, total and individual bile acids secretion accompanied by a biliary leakage of lactate dehydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid and taurocholic acid, on the contrary, were choleretic, inducing an opposite effect on biliary parameters. Simultaneous infusion of taurochenodeoxycholic acid and the protective bile acid resulted in a functional and morphological improvement of the above parameters in the following order: glycine ursodeoxycholic acid > tauroursodeoxycholic acid > ursodeoxycholic acid followed by taurocholic acid; cholic acid was ineffective. CONCLUSIONS: The results show the protective effect of glycine ursodeoxycholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid. This may be due to a facilitated transport of the toxic bile acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protective effect of ursodeoxycholic acid and its amidates with respect to cholic acid and its taurine conjugated form seems to be related to their different lipophilicity and micellar forming capacity.

Alkaline Phosphatase↗

PubMed1986

Conjugated bile acid and cholesterol levels in pregnant Africans and Caucasians.

Pregnancy serum glycochenodeoxycholic acid (GCDA) and taurochenodeoxycholic acid (TCDA) were simultaneously assayed by solid-phase fluoroimmunoassay (FIA) for apparently healthy Nigerians and caucasians domiciled in Nigeria and London respectively. Serum cholesterol values were also obtained for the same gestational period, that is, the second and third trimesters. The bile acid and cholesterol values were compared with those of their respective non-pregnant counterparts. Although there was a considerable fluctuation in the mean bile acid concentrations throughout this period for both pregnant groups, the mean bile acid value for each group was, however, within the normal range. The mean bile acid concentration for the pregnant African was significantly lower than that of her Caucasian counterpart, a notable factor in the assessment of hepatobiliary function for the African during pregnancy. Furthermore, a progressive rise in serum cholesterol during pregnancy, previously observed by other workers, was confirmed for both groups of women. But the increase in cholesterol concentration, which was greater in the Caucasian than the African, did not, however, appear to have affected the bile acid concentration during pregnancy.

Adult↗

PubMed1977

Sterol metabolism studies in the rat. Effects of primary bile acids (sodium taurochenodeoxycholate and sodium taurocholate) on sterol metabolism.

Sterol metabolism studies using a combination of isotopic and chromatographic procedures were carried out in rats fed either a low-cholesterol stock diet or a stock diet containing 0.1% cholesterol. The primary bile acids, sodium taurochenodeoxycholate and sodium taurocholate, were added to the stock diets at a level of 0.5%, as required. Feeding sodium taurochenodeoxycholate and sodium taurocholate led to a decrease in acidic steroid synthesis, cholesterol turnover, and cholesterol balance, compared to controls. Sodium taurochenodeoxycholate feeding did not influence cholesterol absorption, but rats fed sodium taurocholate showed a twofold increase in cholesterol absorption as well as an accumulation of cholesterol in the liver. Rats receiving diets containing sodium taurochenodeoxycholate or sodium taurocholate plus cholesterol (0.1%) showed decreased acidic steroid synthesis, cholesterol turnover, and cholesterol balance, compared to the corresponding controls (Group 2, high cholesterol diet). Significantly larger amounts of cholesterol were absorbed in the taurocholate group (34.1 mg/day); these animals increased their concentrations of cholesterol in liver and plasma. The rats fed taurocholate plus 0.1% cholesterol differed from those fed taurochenodeoxycholate plus 0.1% cholesterol in the following respects: a) increased cholesterol absorption (35%), and b) accumulation of cholesterol in liver and plasma.

Animals↗

PubMed1999

Tauroursodeoxycholic acid enhances phagocytosis of the cultured rat Kupffer cell.

BACKGROUND: Ursodeoxycholic acid is used in the treatment of acute and chronic intrahepatic cholestasis because it ameliorates cholestasis and protects hepatocytes. However, few studies have examined the effect of bile acids on the function of Kupffer cells. METHODS: The effect of various bile acids on cultured rat Kupffer cells was studied in terms of phagocytic activity in response to latex particles and morphological alterations. Video-enhanced differential interference contrast microscopy was used. RESULTS: Taurochenodeoxycholic acid and taurodeoxycholic acid reduced the number of latex particles incorporated into Kupffer cells, but taurocholic and tauroursodeoxycholic acids enhanced phagocytosis of latex particles. Inhibition of phagocytosis by taurochenodeoxycholic acid or taurodeoxycholic acid was essentially dose dependent. Tauroursodeoxycholic acid also enhanced phagocytosis by Kupffer cells in which phagocytosis had been reduced by pretreatment with taurochenodeoxycholic acid or taurodeoxycholic acid. Incorporated latex particles had a distinct translocation speed of 0.084+/-0.024 microm/s (mean maximum speed+/-SD); the speed was in the same range with tauroursodeoxycholic acid treatment. Tauroursodeoxycholic acid induced a 56% expansion of cytoplasm, associated with increased ruffling and movement of intracellular organelles. CONCLUSIONS: These observations suggest that tauroursodeoxycholic acid enhances membrane trafficking without changing translocation speed.

Animals↗

PubMed2007

Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha.

MUC4 (mucin 4) is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701-708]. HNF (hepatocyte nuclear factor) 1alpha and HNF4alpha transcription factors are known to mediate bile acid effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1alpha and HNF4alpha expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1alpha and HNF4alpha were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1alpha regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at -3332/-3327 and -3040/-3028 in the distal promoter. We also showed by siRNA (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1alpha mediates taurodeoxycholic and taurochenodeoxycholic bile acid activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1alpha is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.

Bile Reflux↗

PubMed1984

The effect of neurotensin on the concentration of cholesterol and bile acids in the guinea pig.

In guinea pigs, total plasma cholesterol concentrations increased above the control values after single intravenous injections and after 3 days of continuous subcutaneous administration of neurotensin (NT). A high dose of NT (125 pmol/100 g body weight) induced tachycardia and severe respiratory distress; the lowest dose (1.25 pmol/100 g body weight) had the greatest hypercholesterolemic effect 15 min after the injections. The bulk of the total plasma cholesterol was in low density lipoprotein fractions. Cholesterol increased in the same fractions after intravenous administrations of NT. NT induced a decrease in the cholesterol content in the ileum but did not affect significantly the cholesterol content in the liver, kidneys or adrenals. In 48-hr fasted controls, plasma cholesterol concentration and cholesterol content in the liver, kidneys, adrenals and terminal ileum increased; after intravenous injections of NT, plasma cholesterol concentration further increased but cholesterol content of the liver, kidneys and ileum decreased. In fed animals, the concentration of the biliary taurochenodeoxycholic acid increased above the control values 5 and 35 min after the intravenous injections of NT. In fasted controls, the total concentration of bile acids was higher than in fed controls, but only the concentration of taurochenodeoxycholic acid further increased after the injections of NT. Proportionately more taurochenodeoxycholic acid than cholesterol was present in bile after the intravenous injections of NT. These data are consistent with the hypothesis that NT has a regulatory role in intestinal cholesterol transport.

Animals↗