The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity.
Jean Claude Ourlin,Frédéric Lasserre,Thierry Pineau,Jean Michel Fabre,Antonio Sa-Cunha,Patrick Maurel,Marie-José Vilarem,Jean-Marc Pascussi +7 more
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TLDR
An elaborate regulatory cascade, tightly controlled by SHP, is revealed for both the maintenance of bile acid production and detoxification in the liver, as well as in vivo in mice.Abstract:
SHP (small heterodimer partner, NR1I0) is an atypical orphan member of the nuclear receptor subfamily in that it lacks a DNA-binding domain. It is mostly expressed in the liver, where it binds to and inhibits the function of nuclear receptors. SHP is up-regulated by primary bile acids, through the activation of their receptor farnesoid X receptor, leading to the repression of cholesterol 7alpha-hydroxylase (CYP7alpha) expression, the rate-limiting enzyme in bile acid production from cholesterol. PXR (pregnane X receptor, NR1I2) is a broad-specificity sensor that recognizes a wide variety of synthetic drugs as well as endogenous compounds such as bile acid precursors. Upon activation, PXR induces CYP3A and inhibits CYP7alpha, suggesting that PXR can act on both bile acid synthesis and elimination. Indeed, CYP7alpha and CYP3A are involved in biochemical pathways leading to cholesterol conversion into primary bile acids, whereas CYP3A is also involved in the detoxification of toxic secondary bile acid derivatives. Here, we show that PXR is a target for SHP. Using pull-down assays, we show that SHP interacts with both murine and human PXR in a ligand-dependent manner. From transient transfection assays, SHP is shown to be a potent repressor of PXR transactivation. Furthermore, we report that chenodeoxycholic acid and cholic acid, two farnesoid X receptor ligands, induce up-regulation of SHP and provoke a repression of PXR-mediated CYP3A induction in human hepatocytes as well as in vivo in mice. These results reveal an elaborate regulatory cascade, tightly controlled by SHP, for both the maintenance of bile acid production and detoxification in the liver.read more
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
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Rifampicin Does not Significantly Affect the Expression of Small Heterodimer Partner in Primary Human Hepatocytes
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References
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Derek J. Parks,Steven G. Blanchard,Randy K. Bledsoe,Gyan Chandra,Thomas G. Consler,Steven A. Kliewer,Julie B. Stimmel,Timothy M. Willson,Ann Marie Zavacki,David D. Moore,Jürgen M. Lehmann +10 more
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Journal ArticleDOI
A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis
Bryan Goodwin,Stacey A. Jones,Roger R. Price,Michael A. Watson,D.D. McKee,Linda B. Moore,Cristin M. Galardi,Joan G. Wilson,Michael C. Lewis,Matthew E. Roth,Patrick R. Maloney,Timothy M. Willson,Steven A. Kliewer +12 more
TL;DR: A potent, nonsteroidal FXR ligand is used to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain that provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Journal ArticleDOI
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
Jürgen M. Lehmann,David D. McKee,Michael A. Watson,Timothy M. Willson,John T. Moore,Steven A. Kliewer +5 more
TL;DR: The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.
Journal ArticleDOI
An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
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