scholarly journals Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

1991 ◽  
Vol 275 (2) ◽  
pp. 501-505 ◽  
Author(s):  
H M Princen ◽  
P Meijer ◽  
B G Wolthers ◽  
R J Vonk ◽  
F Kuipers
Keyword(s):  
Bile Acid ◽  
Cyclosporin A ◽  
Bile Acids ◽  
Chenodeoxycholic Acid ◽  
Alternative Pathway ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Liver Mitochondria ◽  
Bile Acid Synthesis ◽  
Rat Liver Mitochondria

Bile acid synthesis, determined by conversion of [4-14C]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52% (rat) and 45% (human) inhibition of 10 microM. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of beta-muricholic and chenodeoxycholic acids (-64% at 10 microM-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4 microM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.

scholarly journals Selective inhibition of mitochondrial 27-hydroxylation of bile acid intermediates and 25-hydroxylation of vitamin D3 by cyclosporin A

1993 ◽  
Vol 293 (1) ◽  
pp. 203-206 ◽  
Author(s):  
H Dahlbäck-Sjöberg ◽  
I Björkhem ◽  
H M Princen
Keyword(s):  
Bile Acid ◽  
Cyclosporin A ◽  
Chenodeoxycholic Acid ◽  
Vitamin D3 ◽  
Kinetic Studies ◽  
Selective Inhibition ◽  
Acid Synthesis ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Alpha 7

It was demonstrated recently that cyclosporin A blocks bile acid synthesis in cultured rat and human hepatocytes by specific inhibition of chenodeoxycholic acid formation. The site of inhibition was found to be the 27-hydroxylation of cholesterol catalysed by the liver mitochondrial 27-hydroxylase [Princen, Meijer, Wolthers, Vonk and Kuipers (1991) Biochem J. 275, 501-505]. In this paper the mechanism by which cyclosporin A blocks mitochondrial 27-hydroxylation was further investigated. It is shown that cyclosporin A inhibited 27-hydroxylation of bile acid intermediates, depending on their polarity. In isolated rat liver mitochondria, 27-hydroxylation of cholesterol was dose-dependently blocked by the drug, giving half-maximal inhibition at 4 microM, whereas 27-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol was not affected. A similar observation was made using electrophoretically homogeneous cytochrome P-450(27) isolated from rabbit liver mitochondria, excluding the possibility that cyclosporin A interfered with transport of substrates into the mitochondrion. Kinetic studies showed that inhibition of the 27-hydroxylation of cholesterol by cyclosporin A was of a non-competitive type. The drug also inhibited the 25-hydroxylase activity towards vitamin D3, catalysed by the same enzyme preparation, to the same extent as 27-hydroxylation of cholesterol. These results suggest that cyclosporin A may interfere with binding of cholesterol, but not of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol, to the active site of the enzyme. These data provide an explanation for the selective inhibition of chenodeoxycholic acid synthesis.

scholarly journals Transport of Cholesterol into Mitochondria Is Rate-limiting for Bile Acid Synthesis via the Alternative Pathway in Primary Rat Hepatocytes

2002 ◽  
Vol 277 (50) ◽  
pp. 48158-48164 ◽  
Author(s):  
William M. Pandak ◽  
Shunlin Ren ◽  
Dalila Marques ◽  
Elizabeth Hall ◽  
Kaye Redford ◽  
...  
Keyword(s):  
Bile Acid ◽  
Alternative Pathway ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Primary Rat Hepatocytes ◽  
Rate Limiting

scholarly journals Dexamethasone regulates bile acid synthesis in monolayer cultures of rat hepatocytes by induction of cholesterol 7α-hydroxylase

1989 ◽  
Vol 262 (1) ◽  
pp. 341-348 ◽  
Author(s):  
H M Princen ◽  
P Meijer ◽  
B Hofstee
Keyword(s):  
Enzyme Activity ◽  
Bile Acid ◽  
Bile Acids ◽  
Steroid Hormones ◽  
Mrna Level ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hydroxylase Activity ◽  
Acid Pathway

To study the effect of steroid hormones on bile acid synthesis by cultured rat hepatocytes, cells were incubated with various amounts of these compounds during 72 h and conversion of [4-14C]cholesterol into bile acids was measured. Bile acid synthesis was stimulated in a dose-dependent way by glucocorticoids, but not by sex steroid hormones, pregnenolone or the mineralocorticoid aldosterone in concentrations up to 10 microM. Dexamethasone proved to be the most efficacious inducer, giving 3-fold and 7-fold increases in bile acid synthesis during the second and third 24 h incubation periods respectively, at a concentration of 50 nM. Mass production of bile acids as measured by g.l.c. during the second day of culture (28-52 h) was 2.2-fold enhanced by 1 microM-dexamethasone. No change in the ratio of bile acids produced was observed during this period in the presence of dexamethasone. Conversion of [4-14C]7 alpha-hydroxycholesterol, an intermediate of the bile acid pathway, to bile acids was not affected by dexamethasone. Measurement of cholesterol 7 alpha-hydroxylase activity in homogenates of hepatocytes, incubated with 1 microM-dexamethasone, showed 10-fold and 90-fold increases after 48 and 72 h respectively, as compared with control cells. As with bile acid synthesis from [14C]cholesterol, no change in enzyme activity was found in hepatocytes cultured in the presence of 10 microM steroid hormones other than glucocorticoids. Addition of inhibitors of protein and mRNA synthesis lowered bile acid production and cholesterol 7 alpha-hydroxylase activity and prevented the rise of both parameters with dexamethasone, suggesting regulation at the mRNA level. We conclude that glucocorticoids regulate bile acid synthesis in rat hepatocytes by induction of enzyme activity of cholesterol 7 alpha-hydroxylase.

Bile acid synthesis in isolated rat hepatocytes

1978 ◽  
Vol 56 (8) ◽  
pp. 780-783 ◽  
Author(s):  
I. M. Yousef ◽  
J. Ho ◽  
K. N. Jeejeebhoy
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Isolated Hepatocytes ◽  
Bile Acid Synthesis ◽  
Isolated Rat Hepatocytes ◽  
Adult Rat ◽  
Vitro Model

Normal adult rat hepatocytes were incubated for 48 h and the concentration of total and individual bile acids in homogenized samples of the culture was measured at intervals during the incubation, using radiogas chromatography and isotope derivative assay. The net increase in bile acids over the value observed at the start of the culture was taken as synthesis. The results showed that bile acid synthesis was linear up to 24 h of incubation, at a rate of 20 nmol/g hepatocytes per hour, and that 85% of the newly synthesized bile acid was cholic acid. The bile acid synthesized was mainly conjugated with taurine. These results suggest that isolated hepatocytes cultured in the way described could be a useful in vitro model for the study of bile acid synthesis.

scholarly journals Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels

2009 ◽  
Vol 297 (1) ◽  
pp. G144-G151 ◽  
Author(s):  
Katie T. Burke ◽  
Paul S. Horn ◽  
Patrick Tso ◽  
James E. Heubi ◽  
Laura A. Woollett
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Alternative Pathway ◽  
Newborn Infants ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
Mrna Levels ◽  
Bile Acid Pool ◽  
Acid Pool

Intraluminal concentrations of bile acids are low in newborn infants and increase rapidly after birth, at least partly owing to increased bile acid synthesis rates. The expansion of the bile acid pool is critical since bile acids are required to stimulate bile flow and absorb lipids, a major component of newborn diets. The purpose of the present studies was to determine the mechanism responsible for the increase in bile acid synthesis rates and the subsequent enlargement of bile acid pool sizes (BAPS) during the neonatal period, and how changes in circulating hormone levels might affect BAPS. In the hamster, pool size was low just after birth and increased modestly until 10.5 days postpartum (dpp). BAPS increased more significantly (∼3-fold) between 10.5 and 15.5 dpp. An increase in mRNA and protein levels of cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting step in classical bile acid synthesis, immediately preceded an increase in BAPS. In contrast, levels of oxysterol 7α-hydroxylase (Cyp7b1), a key enzyme in bile acid synthesis by the alternative pathway, were relatively elevated by 1.5 dpp. farnesyl X receptor (FXR) and short heterodimeric partner (SHP) mRNA levels remained relatively constant at a time when Cyp7a1 levels increased. Finally, although simultaneous increases in circulating cortisol and Cyp7a1 levels occurred, precocious expression of Cyp7a1 could not be induced in neonatal hamsters with dexamethasone. Thus the significant increase in Cyp7a1 levels in neonatal hamsters is due to mechanisms independent of the FXR and SHP pathway and cortisol.

scholarly journals Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes

1995 ◽  
Vol 305 (2) ◽  
pp. 505-511 ◽  
Author(s):  
J Twisk ◽  
E C M de Wit ◽  
H M G Princen
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Transcriptional Activity ◽  
Lithocholic Acid ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Taurocholic Acid ◽  
Substantial Contribution ◽  
Cultured Rat Hepatocytes

In previous work we have demonstrated suppression of cholesterol 7 alpha-hydroxylase by bile acids at the level of mRNA and transcription, resulting in a similar decline in bile acid synthesis in cultured rat hepatocytes [Twisk, Lehmann and Princen (1993) Biochem. J. 290, 685-691]. In view of the substantial contribution of the ‘alternative’ or ‘27-hydroxylase’ route to total bile acid synthesis, as demonstrated in cultured rat hepatocytes and in vivo in humans, we here evaluate the effects of various bile acids commonly found in bile of rats on the regulation of sterol 27-hydroxylase in cultured rat hepatocytes. Addition of taurocholic acid, the predominant bile acid in rat bile, to the culture medium of rat hepatocytes resulted in a 72% inhibition of sterol 27-hydroxylase activity. The effect was exerted at the level of sterol 27-hydroxylase mRNA, showing a time- and dose-dependent decline with a maximal suppression (-75%) at 50 microM taurocholic acid after 24 h of culture. The decline in mRNA followed first-order kinetics with an apparent half-life of 13 h. Under these conditions cholesterol 7 alpha-hydroxylase mRNA (-91%) and bile acid synthesis (i.e. chenodeoxycholic and beta-muricholic acid, -81%) were also maximally suppressed. In contrast, no change was found in the level of lithocholic acid 6 beta-hydroxylase mRNA. Assessment of the transcriptional activity of a number of genes involved in routing of cholesterol towards bile acids showed similar suppressive effects of taurocholate on expression of the sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase genes (-43% and -42% respectively), whereas expression of the lithocholic 6 beta-hydroxylase gene was not affected. Taurocholic acid and unconjugated cholic acid were equally as effective in suppressing sterol 27-hydroxylase mRNA. The more hydrophobic bile acids, chenodeoxycholic acid and deoxycholic acid, also produced a strong inhibition of 57% and 76% respectively, whereas the hydrophilic beta-muricholic acid was not active. We conclude that (1) a number of bile acids, at physiological concentrations, suppress sterol 27-hydroxylase by down-regulation of sterol 27-hydroxylase mRNA and transcriptional activity and (2) co-ordinated suppression of both sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase results in inhibition of bile acid synthesis in cultured rat hepatocytes.

scholarly journals Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

2021 ◽  
Author(s):  
Akihiko Kimura ◽  
Tatsuki Mizuochi ◽  
Hajime Takei ◽  
Akira Ohtake ◽  
Jun Mori ◽  
...  
Keyword(s):  
Bile Acid ◽  
Chenodeoxycholic Acid ◽  
Acid Treatment ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea

2021 ◽  
Vol 12 (2) ◽  
pp. 335-353
Author(s):  
Evette B. M. Hillman ◽  
Sjoerd Rijpkema ◽  
Danielle Carson ◽  
Ramesh P. Arasaradnam ◽  
Elizabeth M. H. Wellington ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gastrointestinal Disease ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
The United Kingdom ◽  
The 1960S ◽  
Irritable Bowel ◽  
The Uk

Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.

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