Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei

Setchell, Kenneth D.R.; Rodrigues, Cecília M. P.; Clerici, Carlo; Solinas, Attilio; Morelli, Antonio; Gartung, Carsten; Boyer, James L.

doi:10.1016/s0016-5085(97)70239-7

Cited by 176 publications

(136 citation statements)

References 7 publications

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“…Using a highly efficient and sensitive LC/MS-based method, we have found an increase in conjugated CA, a dominant primary bile acid in normal rodent bile. This is consistent with previous studies in the rat (32), although an early transient increase in unconjugated CA has also been observed (36).…”

Section: Figsupporting

confidence: 93%

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

Stedman

Robertson

Coulter

et al. 2004

Journal of Biological Chemistry

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Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5 regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6␤-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

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Section: Figsupporting

confidence: 93%

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

Stedman

Robertson

Coulter

et al. 2004

Journal of Biological Chemistry

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“…LCA is a highly toxic secondary bile acid that causes cholestasis, a pathogenic state characterized by decreased bile flow and the accumulation of bile constituents in the liver and blood (13,32). Notably, LCA concentrations of 5-10 M have been reported in the livers of cholestatic patients and in rat models of biliary cholestasis (33). Because LCA activates PXR at these concentrations, we examined whether PXR Ϫ/Ϫ mice showed defects in LCA metabolism.…”

Section: Resultsmentioning

confidence: 99%

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Staudinger

Goodwin

Jones

et al. 2001

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

1,219

1,099

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The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16␣-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7␣-hydroxylase (Cyp7a1) and the Na ؉ -independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

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“…17,43 However, this mechanism remains to be determined for ␤-muricholic acid, the major bile acid accumulating in rodents following CBDL. 32,44 HNF-1␣ and the RXR␣:RAR␣ heterodimer complex have been identified as the major transactivators of rat Ntcp. 10,14 In contrast, regulation of the mouse Ntcp promoter by HNF-1␣ and RXR␣:RAR␣ was recently questioned by Jung et al, 45 who did not identify respective response elements in a minimal mouse Ntcp promoter.…”

Section: Discussionmentioning

confidence: 99%