Chenodeoxycholate: The Bile Acid. The Drug. A Review

Broughton, George

doi:10.1097/00000441-199401000-00011

Cited by 15 publications

(7 citation statements)

References 52 publications

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“…What the full in vivo role of FXR is, and whether bile acids are endogenous ligands for the FXR in all these tissues remains to be seen. Bile acids do have a wide range of effects; CDCA dissolves cholesterol gallstones and is used for the management of cerebrotendinous xanthomatosis, hypertriglyceremia, congenital liver diseases, rheumatoid arthritis, and constipation (30). It is tempting to speculate that some of these effects are mediated by FXR.…”

Section: Discussionmentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

211

163

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The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

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Section: Discussionmentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

211

163

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“…the formation of hydroxymethylglutaryl-coenzyme A. Furthermore, chenodeoxycholic acid is also involved in the management of hypertriglyceridernia, congenital liver disease, rheumatoid arthritis and constipation (4).…”

Section: Introductionmentioning

confidence: 99%

Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3α,7α-dihydroxy-12-0X0-5β-cholanate, in healthy and diabetic rats

Mikov

Boni

Al‐Salami

et al. 2007

Eur. J. Drug Metabol. Pharmacokinet.

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Previous studies in our laboratory have shown that the semisynthetic bile acid derivative, sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate (MKC), has hypoglycemic activity. The aim of this study was to investigate the relationship between the pharmacokinetics and hypoglycemic activity of MKC in healthy and diabetic rats. Groups of healthy and alloxan-induced diabetic rats were dosed intravenously (i.v.) and orally with MKC (4 mg/kg). Blood samples were taken before administration of the dose and at 20, 40, 60, 80, 120, 150, 180, 210 and 240 minutes post-dose. MKC serum concentration was measured by HPLC, and pharmacokinetic parameters determined using the WinNonlin program. The absolute bioavailability of MKC was found to be low in healthy and diabetic rats (29 and 23% respectively) and was not significantly different between the two groups. Mean residence time (MRT), volume of distribution (Vd) and half-life (t1/2) of MKC after oral administration were significantly lower in diabetic than in healthy rats (21, 31 and 29% respectively). After the i.v. dose, the change in blood glucose concentration was not significant in either healthy or diabetic rats. After the oral dose, the decrease in blood glucose concentration was significant, reaching a maximum decrease from baseline of 24% in healthy rats and 15% in diabetic rats. The results suggest that a first-pass effect is crucial for the hypoglycemic activity of MKC, indicating that a metabolite of MKC and/or interference with metabolism and glucose transport is responsible.

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“…In 1999, three laboratories made the important and unexpected observation that bile acids function as ligand activators for both rodent and human FXR (8)(9)(10). Chenodeoxycholate (CDCA) (8-10), a primary bile acid that is synthesized in the liver as a result of oxidation and catabolism of cholesterol, is the most potent ligand for FXR (11). At the present time, primary response genes that are known Abbreviations: apoC-II, Apolipoprotein C-II; CDCA, chenodeoxycholic acid; DMSO, dimethylsulfoxide; EcRE, Ecdysone response element; FXR, farnesoid X-activated receptor; FXRE, FXR response element; HCR, hepatic control region; IR-I, inverted repeat with one nucleotide spacing between the two half-sites; IRES, internal ribosome entry site; LCA, lithocholic acid; SHP, small heterodimer partner; SSH, suppression subtractive hybridization; TK, thymidine kinase; TTNPB,…”

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confidence: 99%

Farnesoid X-Activated Receptor Induces Apolipoprotein C-II Transcription: a Molecular Mechanism Linking Plasma Triglyceride Levels to Bile Acids

Kast

Nguyen

Sinal

et al. 2001

Molecular Endocrinology

255

116

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The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid- containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias.

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Chenodeoxycholate: The Bile Acid. The Drug. A Review

Cited by 15 publications

References 52 publications

Expression and activation of the farnesoid X receptor in the vasculature

Expression and activation of the farnesoid X receptor in the vasculature

Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3α,7α-dihydroxy-12-0X0-5β-cholanate, in healthy and diabetic rats

Farnesoid X-Activated Receptor Induces Apolipoprotein C-II Transcription: a Molecular Mechanism Linking Plasma Triglyceride Levels to Bile Acids

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