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 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 Maintenance of bile acid synthesis and cholesterol 7α-hydroxylase activity in cultured rat hepatocytes

1990 ◽  
Vol 272 (1) ◽  
pp. 273-275 ◽  
Author(s):  
H M G Princen ◽  
P Meijer
Keyword(s):  
Bile Acid ◽  
Bovine Serum ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hydroxylase Activity ◽  
Newborn Bovine Serum ◽  
Cultured Rat Hepatocytes ◽  
Synthetic Capacity ◽  
Foetal Bovine Serum

Addition of foetal-bovine serum to rat hepatocytes cultured in Williams E medium resulted in improved maintenance of bile-acid-synthetic capacity and cholesterol 7 alpha-hydroxylase activity as compared with cultures supplemented with rat or newborn-bovine serum or cultures in a hormonally defined serum-free medium. Minimally, 5% (v/v) foetal-bovine serum was necessary to maintain these liver-specific functions. Serum factor(s) responsible for these effects were not dialysable or associated with lipoproteins, but were removed by charcoal extraction.

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 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.

scholarly journals Liver Bile Acid Changes in Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7451
Author(s):  
Harpreet Kaur ◽  
Drew Seeger ◽  
Svetlana Golovko ◽  
Mikhail Golovko ◽  
Colin Kelly Combs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

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