Mechanisms of Bile Acid Biosynthesis

Danielsson, Henry

doi:10.1007/978-1-4684-0898-0_1

Cited by 47 publications

(32 citation statements)

References 161 publications

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“…Earlier, Shefer et al (6) suggested that TCA inhibited bile-acid synthesis via the suppression of CH7aH, but these results were confounded by similar changes in HMGR. Thus, reduced bile-acid synthesis could have reflected decreased availability of cholesterol for it is unequivocally established in mammals that cholesterol is the sole precursor of bile acids (1). In this experimental design, newly synthesized cholesterol was provided by infusing mevalonolactone so that bile-acid synthesis could be studied independently of the activity of HMGR, the rate-controlling enzyme of cholesterol synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…Cholesterol' is the obligate precursor of bile acids in mammals (1). According to current information, the conversion of cho-by trivial names: cholesterol, 5-cholesten-33-ol; 7a-hydroxycholesterol, 5-cholestene-3f,7a-diol; taurocholic acid, 2-[[3a,7a, 12a-trihydroxy-24-oxo-53-cholan-24-yl]aminolethanesulfonic acid; tauroursocholic acid, 2-[[3a,73, 1 2a-trihydroxy-24-oxo-5f3-cholan-24-yl]amino]ethanesulfonic acid; lithocholic acid, 3a-hydroxy-5,3-cholan-24-oic acid; deoxycholic acid, 3a, 12a-dihydroxy-50-cholan-24-oic acid; chenodeoxycholic acid, 3a,7a-dihydroxy-513-cholan-24-oic acid; a-muricholic acid, 3a,63,7a-trihydroxy-51-cholan-24-oic acid; cholic lesterol to 7a-hydroxycholesterol is the rate-determining step of bile-acid synthesis and is catalyzed by the enzyme cholesterol 7a-hydroxylase (CH7aH)2 which is located in the hepatic smooth endoplasmic reticulum (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

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Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate.

Shefer¹,

Nguyen²,

Salen³

et al. 1990

J. Clin. Invest.

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We studied the effect of the orientation of the 7-hydroxyl group in taurocholate (7a) and tauroursocholate (7ft) on the feedback regulation of bile-acid synthesis and its rate-controlling enzyme, cholesterol 7a-hydroxylase, in bile-fistula rats. To ensure a constant supply of cholesterol and to label newly synthesized bile acids, RS[2-'4Clmevalonolactone was infused intraduodenally at 154 ,imol/h before and during bile-acid infusion. Mevalonolactone inhibited hydroxymethyl-glutaryl CoA reductase activity 90% but did not increase bile-acid synthesis and cholesterol 7a-hydroxylase activity. When sodium taurocholate was infused at the rate of 27 ,umol/100 g rat per h (equivalent to the hourly hepatic bile-acid flux), bile-acid synthesis decreased 82% and cholesterol 7a-hydroxylase activity declined 78%. This inhibitory effect was observed in the absence of hepatic damage. In contrast, sodium tauroursocholate infused at the same rate did not decrease bile-acid synthesis nor cholesterol 7a-hydroxylase activity. Hepatic cholesterol content rose 36% with sodium taurocholate but did not change during sodium tauroursocholate administration. These results demonstrate that the feedback inhibition of bile-acid synthesis is mediated through the regulation of cholesterol 7a-hydroxylase. In these experiments, taurocholate was a far more potent inhibitor than its 70-hydroxy epimer, tauroursocholate. (J.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate.

Shefer¹,

Nguyen²,

Salen³

et al. 1990

J. Clin. Invest.

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“…According to current concepts of the biosynthesis of bile acids from cholesterol in mammalian liver, the changes Receivcd for publication 17 September 1974 and in revised form 4 November 1974. in the steroid nucleus precede the degradation of the steroid side chain (1), and 5j3-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol have been postulated as intermediates in the biosynthesis of cholic acid1 and chenodeoxycholic acid,' respectively. The sequence of reactions leading to the formation of 5,8-cholestane-3a,7a-diol in rat liver (1), guinea pig liver (2), as well as human liver (3) appears to be the following: cholesterol -> 5-cholestene-3fi,7a-diol --7a-hydroxy-4-cholesten-3-one -> 7a-hydroxy-5P-cholestan-3-one > 5P-cholestane3a,7a-diol.…”

Section: Introductionmentioning

confidence: 99%

“…The sequence of reactions leading to the formation of 5,8-cholestane-3a,7a-diol in rat liver (1), guinea pig liver (2), as well as human liver (3) appears to be the following: cholesterol -> 5-cholestene-3fi,7a-diol --7a-hydroxy-4-cholesten-3-one -> 7a-hydroxy-5P-cholestan-3-one > 5P-cholestane3a,7a-diol. In the sequence of reactions leading to 59-cholestane-3a,7a,12a-triol, a 12a-hydroxyl group is introduced, probably at the stage of 7a-hydroxy-4-cholesten- 3-one (1). The mechanisms of degradation of the side chains in 5,8-cholestane-3a,7a-diol and 53-cholestane-3a,-7a,12a-triol have not been completely established.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms of degradation of the side chains in 5,8-cholestane-3a,7a-diol and 53-cholestane-3a,-7a,12a-triol have not been completely established. Studies in vitro with preparations from rat liver show that in the major pathway for the degradation of the side chain, microsomal and/or mitochondrial 26-hydroxylation is the initial reaction (1,(4)(5)(6)(7). The possibility that side chain degradation starts with a 25-hydroxylation has also been discussed, but there is little experimental evidence as yet to support this pathway.…”

Section: Introductionmentioning

confidence: 99%

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Biosynthesis of bile acids in man. Hydroxylation of the C27-steroid side chain.

Björkhem¹,

Gustafsson

Johansson³

et al. 1975

J. Clin. Invest.

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A B S T R A C T The first step in the degradation of the steroid side chain during biosynthesis of bile acids from cholesterol in man was studied in microsomal and mitochondrial fraction of homogenate of livers from 14 patients.The The mitochondrial fraction was found to catalyze 26-hydroxylation of cholesterol, 5-cholestene-3P,7a-diol, 5P-cholestane-3a,7a-diol, 7a-hydroxy-4-cholesten-3-one, and 5,0-cholestane-3a,7a,12a-triol. Addition of Mg"+ stimulated the 26-hydroxylation of cholesterol but had no effect or an inhibitory effect on 26-hydroxylation of the other substrates, indicating a heterogeneity of the mitochondrial 26-hydroxylating system. The level of 26-hydroxylase activity towards different substrates varied considerably with different mitochondrial preparations.The roles of the microsomal and mitochondrial 26-hydroxylations as well as the microsomal 25-hydroxylation in biosynthesis of bile acids in man are discussed.The results indicate that microsomal 26-hydroxylation is less important than mitochondrial 26-hydroxylation under normal conditions. The possibility that microsomal 25-hydroxylation is important cannot be ruled out.

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Evaluation of 3‐hydroxy‐3‐methylglutaryl‐COA‐reductase, cholesterol‐7α‐hydroxylase and acyl‐COA:cholesterol acyltransferase activities: alternative chromatographic methods to separate metabolites

Montoudis

Boileau

Simoneau

et al. 2004

Biomedical Chromatography

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Alternative HPLC and solid-phase extraction column methods were developed to separate metabolites of enzymes involved in cholesterol metabolism in rabbit liver microsomes: hydroxyl-methylglutaryl-CoA reductase, cholesterol-7alpha-hydroxylase and acyl-CoA:cholesterol acyltransferase. A comparison method of thin-layer chromatography and solid-phase extraction column were assayed to separate substrate and metabolite of hydroxy-methylglutaryl-CoA reductase, whereas for cholesterol-7alpha-hydroxylase and acyl-CoA:cholesterol acyltransferase, this comparison was done between thin layer chromatography and HPLC. The results obtained by the new analytical chromatographic methods are not significantly different than those observed in literature. Moreover a larger percentage recovery was obtained for analysed metabolites. Our results demonstrate the reliability of these alternative chromatographic techniques and showed that they are valuable tools to precisely and rapidly measure the activity of those enzymes.

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Mechanisms of Bile Acid Biosynthesis

Cited by 47 publications

References 161 publications

Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate.

Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate.

Biosynthesis of bile acids in man. Hydroxylation of the C27-steroid side chain.

Evaluation of 3‐hydroxy‐3‐methylglutaryl‐COA‐reductase, cholesterol‐7α‐hydroxylase and acyl‐COA:cholesterol acyltransferase activities: alternative chromatographic methods to separate metabolites

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