Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

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Abstract

Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drug-metabolizing cytochromes P450 (CYPs). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin, and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bile-acid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.

Section snippets

The nuclear receptor NR1I group includes xenosensors and lipid-sensing members

Compounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain structure has not been solved yet, PXR crystal structures provided evidence for the high promiscuity of its ligand-binding pocket [25], [26]. The binding cavity is 1150 Å3 in size, substantially larger than those of many other members of the nuclear receptor superfamily, and has

Xenosensors in steroid biosynthesis and metabolism

Since some of the CYPs that are regulated by PXR and CAR are involved in steroid metabolism, it is not surprising that the activities of both xenosenors are also modulated by steroids [38]: PXR is activated by pregnanes, progesterone, and glucocorticoids [4], [5] whereas androstane metabolites, estrogens, and progesterone affect CAR activity both positively and negatively [10], [39], [40], [41]. Transgenic expression of a human constitutively active VP16-PXR fusion protein in mouse liver

CAR and PXR confer hepatoprotection upon bile acid exposure

Under standard conditions, PXR knockout mice are viable and show no overt phenotype [8]. However, upon challenge with a bile acid-rich diet, PXR null animals suffer from a higher degree of bile acid-induced hepatotoxicity compared to wild-type littermates [50], [51]. Certain bile acids (e.g., lithocholic acid) have been shown to directly activate PXR at concentrations between 10 and 100 μM [50], [51]. Moreover, three bile acid precursors (7α-hydroxy-4-cholesten-3-one,

Nuclear receptor regulation of cholesterol biosynthesis and metabolism

Cholesterol is metabolized by two different pathways. The “classic” bile acid biosynthesis pathway is exclusively found in the liver and results in the formation of the primary bile acids cholic acid and chenodeoxycholic acid. The “alternative” pathway is ubiquitous and produces oxidized cholesterols which have to be transported to the liver in order to be converted into bile acids. Under normal conditions, the classic pathway is the main bile acid biosynthetic pathway in the liver [58], [59],

NR1I subfamily members regulate lipid levels in the liver

In addition to cholesterol and bile acid homeostasis, LXR and FXR play diametrically opposed roles in the regulation of lipid biosynthesis. LXR is a strong activator of SREBP-1c and thus triggers an increase in triglyceride biosynthesis in the liver [103], [104]. Moreover, independent of SREBP-1c, LXR directly activates other lipogenic genes including fatty acid synthase (FAS) [105]. In contrast, FXR transcription is increased in the fasting liver by the peroxisome proliferator activated

Experimental and clinical observations

A functional link between xenobiotics and lipid levels has been confirmed by a number of observations and findings in cell culture, animals and patients. As examples, blocking of de novo cholesterol biosynthesis using different inhibitors such as squalestatin, lovastatin or fluvastatin increases CYP2B1/2 in rat primary hepatocytes and in rat liver in vivo [117], [118], [119]. Phenobarbital-treatment of rats changed the expression of various genes in the cholesterol-biosynthesis pathway [120],

Species differences in hepatic detoxification

Marked differences in the way different species deal with foreign compounds have been described [53], [142]. First, CYP orthologs differ in their basal expression in different species: e.g., CYP3As are very abundant in humans and key enzymes in steroid and xenobiotic metabolism whereas CYP3A levels, in the absence of induction, are relatively low in rodents [143]. In addition, these genes are differentially induced by drugs and other xenobiotics. As example, human, but not rodent CYP3As are

Conclusions

Although it appears paradoxical because the potential for drug–drug interactions and adverse drug reactions may increase [153], therapeutic targeting of CAR and PXR might be beneficial under certain conditions. Inhibition of CAR either by genetic ablation or by using CAR inverse agonists decreases acetaminophen-induced hepatotoxicity [154]. On the other hand, increasing CAR activity most likely ameliorates neonatal jaundice by increasing bilirubin conjugation and clearance [155]. Moreover,

Acknowledgments

C.H. is supported by the “Schweizerische Stiftung für Medizinisch-Biologische Stipendien,” the Swiss Academy of Medical Sciences and the Swiss National Science Foundation. U.A.M. is supported by the Swiss National Science Foundation.

References (157)

  • S.A. Kliewer et al.

    Cell

    (1998)
  • L.B. Moore et al.

    J. Biol. Chem.

    (2000)
  • J.T. Moore et al.

    Biochim. Biophys. Acta

    (2003)
  • S. Kakizaki et al.

    Biochim. Biophys. Acta

    (2003)
  • J.M. Pascussi et al.

    Biochim. Biophys. Acta

    (2003)
  • F. Grün et al.

    J. Biol. Chem.

    (2002)
  • D.J. Mangelsdorf et al.

    Cell

    (1995)
  • D.J. Mangelsdorf et al.

    Cell

    (1995)
  • H. Wang et al.

    Mol. Cell

    (1999)
  • L. You

    Chem. Biol. Interact.

    (2004)
  • G.L. Guo et al.

    J. Biol. Chem.

    (2003)
  • M. Assem et al.

    J. Biol. Chem.

    (2004)
  • J.Y. Chiang

    J. Hepatol.

    (2004)
  • R.A. Davis et al.

    J. Lipid Res.

    (2002)
  • J.M. Lehmann et al.

    J. Biol. Chem.

    (1997)
  • D.J. Peet et al.

    Cell

    (1998)
  • J.Y. Chiang et al.

    Gene

    (2001)
  • L.B. Agellon et al.

    J. Biol. Chem.

    (2002)
  • J.Y. Chen et al.

    J. Biol. Chem.

    (2002)
  • T.T. Lu et al.

    Mol. Cell

    (2000)
  • B. Goodwin et al.

    Mol. Cell

    (2000)
  • T.A. Kerr et al.

    Dev. Cell

    (2002)
  • L. Wang et al.

    Dev. Cell

    (2002)
  • M. Crestani et al.

    J. Lipid Res.

    (1998)
  • E. De Fabiani et al.

    J. Biol. Chem.

    (2001)
  • H.R. Kast et al.

    J. Biol. Chem.

    (2002)
  • E.G. Schuetz et al.

    J. Biol. Chem.

    (2001)
  • L. Drocourt et al.

    J. Biol. Chem.

    (2002)
  • Z. Araya et al.

    Biochim. Biophys. Acta

    (1999)
  • C. Furster et al.

    Biochim. Biophys. Acta

    (1999)
  • J.C. Ourlin et al.

    Biochem. Biophys. Res. Commun.

    (2002)
  • C. Handschin et al.

    J. Biol. Chem.

    (2002)
  • C. Stedman et al.

    J. Biol. Chem.

    (2004)
  • K. Bodin et al.

    J. Biol. Chem.

    (2001)
  • K. Bodin et al.

    J. Biol. Chem.

    (2002)
  • Z. Zhang et al.

    J. Lipid Res.

    (2001)
  • H. Wietholtz et al.

    J. Hepatol.

    (1996)
  • D.R. Nelson et al.

    Pharmacogenetics

    (1996)
  • H. Remmer

    Naturwissenschaften

    (1958)
  • P. Honkakoski et al.

    Mol. Cell. Biol.

    (1998)
  • J.M. Lehmann et al.

    J. Clin. Invest.

    (1998)
  • B. Blumberg et al.

    Genes Dev.

    (1998)
  • G. Bertilsson et al.

    Proc. Natl. Acad. Sci. USA

    (1998)
  • W. Xie et al.

    Nature

    (2000)
  • P. Wei et al.

    Nature

    (2000)
  • W. Xie et al.

    Genes Dev.

    (2000)
  • P. Wei et al.

    Pharmacogenomics J.

    (2002)
  • J.M. Maglich et al.

    Mol. Pharmacol.

    (2002)
  • S.A. Kliewer et al.

    Endocr. Rev.

    (2002)
  • H. Wang et al.

    Curr. Drug Metab.

    (2003)
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