PXR and the regulation of apoA1 and HDL-cholesterol in rodents

Bachmann, Kenneth; Patel, Hiral; Batayneh, Zaid; Slama, James T.; White, Donald B.; Posey, Julie; Ekins, Sean; Gold, David; Sambucetti, Lidia

doi:10.1016/j.phrs.2004.03.005

Cited by 67 publications

(58 citation statements)

References 32 publications

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“…18 -22 Interestingly, several studies have reported that administration of pharmacological PXR agonists is associated with significant increases in both hepatic apoA-I transcription and circulating levels of apoA-I and HDL cholesterol in rats, mice, and humans. [11][12][13][14][15][37][38][39] The purposes of the present study were: (1) to establish the relative contribution of PXR to the effect of bile acids on plasma lipoprotein profile through the comparison of WT and Pxr-null mice; and (2) to determine whether overexpression of human PXR in Pxr-null SXR-Tg mice was able to counteract the deleterious, FXRmediated effects of bile acids.…”

Section: Discussionmentioning

confidence: 99%

“…Although several ligands of pregnane X receptor (PXR) (NR1I2) were reported to increase HDL cholesterol as well as apoA-I and apoA-I mRNA levels in rodents and humans, [11][12][13][14][15] the relative contribution of PXR to the regulation of plasma HDL levels in vivo remains to be ascertained. Interestingly, besides its role as a xenobiotic sensor, 16 -17 PXR responds to bile acids that also constitute well-recognized FXR ligands.…”

Section: See Page 2016mentioning

confidence: 99%

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Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Masson

Lagrost

Athias

et al. 2005

ATVB

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Objective-Modification of lipoprotein metabolism by bile acids has been mainly explained by activation of the farnesyl X receptor (FXR). The aim of the present study was to determine the relative contribution of the pregnane X receptor (PXR), another bile acid-activated nuclear receptor to changes in plasma lipoprotein profile. Methods and Results-Wild-type mice, Pxr-deficient mice, and Pxr-null mice expressing human PXR (Pxr-null SXR-Tg mice)were fed a cholic acid-containing diet, and consequences on plasma lipoprotein profiles and target gene expression were assessed. Cholic acid produced significant decreases in high-density lipoprotein (HDL) cholesterol, plasma apolipoprotein (apo)A-I and hepatic apoA-I mRNA in wild-type mice. Interestingly, the effect of cholic acid was significantly more pronounced in Pxr-deficient mice, indicating that PXR contributes to the weakening of the effect of bile acids on lipoprotein metabolism. Reciprocally, changes in HDL/apoA-I profiles were abolished in Pxr-null SXR-Tg mice in which PXRresponsive genes, particularly those involved in bile acid detoxification were readily activated after cholic acid treatment. Key Words: apolipoprotein A-I Ⅲ bile acids Ⅲ farnesyl X receptor Ⅲ high-density lipoproteins Ⅲ pregnane X receptor Ⅲ steroid and xenobiotic receptor Conclusion-PXR

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Section: Discussionmentioning

confidence: 99%

Section: See Page 2016mentioning

confidence: 99%

Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Masson

Lagrost

Athias

et al. 2005

ATVB

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“…Interestingly, this elevation of cholesterol and apolipoprotein A1 levels was only observed in wildtype but not in PXR knockout mice [130].…”

Section: Experimental and Clinical Observationsmentioning

confidence: 91%

“…Treatment of rats and with imidazoles also resulted in elevated plasma HDL levels and expression of hepatic apolipoprotein A1 [130]. Interestingly, this elevation of cholesterol and apolipoprotein A1 levels was only observed in wildtype but not in PXR knockout mice [130].…”

Section: Experimental and Clinical Observationsmentioning

confidence: 97%

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

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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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 drugmetabolizing cytochromes P450 (CYP). 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 bileacid-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.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds 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 stru...

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“…In particular, nuclear receptors are associated with the regulation of metabolic homeostasis, through both the action of endosensing receptors such as LXR, FXR and PPAR (Barbier et al, 2002;Mohan and Heyman, 2003), and xenosensing receptors such as PXR and CAR (Bachmann et al, 2004;Pascussi et al, 2008;Wada et al, 2009). Thus, exposure to noncoplanar PCBs may lead to chronic activation of PXR/CAR and potential dysfunction of these metabolic processes.…”

mentioning

confidence: 99%

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

Al-Salman

Plant

2012

Toxicology and Applied Pharmacology

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PXR and the regulation of apoA1 and HDL-cholesterol in rodents

Cited by 67 publications

References 32 publications

Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

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

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

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