Selective activation of liver X receptor alpha by 6Î±-hydroxy bile acids and analogs

Song, Ching; Hiipakka, Richard A.; Liao, Shutsung

doi:10.1016/s0039-128x(00)00127-6

Cited by 110 publications

(66 citation statements)

References 29 publications

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“…In mammals, LXRs are activated by a limited number of bile acids (particularly 6α-hydroxylated bile acids) [6], whereas the related FXRs are activated by a broader diversity of bile acids such as cholic acid (CA) or chenodeoxycholic acid (CDCA) [2]. The bile salts of non-mammalian vertebrates can differ from that of the 24-carbon (C 24 ) bile acids found in the majority of mammals [26,27].…”

Section: Ligand Specificity Of Vertebrate Lxrsmentioning

confidence: 99%

“…LXRs, like other members of the NR1 family, function as permissive heterodimers with the retinoid X receptors (NR2B1, 2B2, and 2B3). LXRs were originally classified as 'orphan' NRs but are perhaps best referred to now as 'adopted orphans' [2], following the identification of endogenous ligands, namely oxysterols such as 24(S)-hydroxycholesterol and 24(S),25-epoxycholesterol [3,4], oxysterol metabolites [5], and some bile acids [6].…”

Section: Introductionmentioning

confidence: 99%

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Ligand specificity and evolution of liver X receptors

Reschly

Ni²,

Welsh³

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity.

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Section: Ligand Specificity Of Vertebrate Lxrsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ligand specificity and evolution of liver X receptors

Reschly

Ni²,

Welsh³

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…Both 6-hydroxylated chenodeoxycholic acid (hyocholic acid) as well as 6-hydroxylated lithocholic -15 -acid (hyodeoxycholic acid) are selective activators of LXR [93,101]. Treatment of hepatoma cells with hyocholic acid or hyodeoxycholic acid reduces the levels of drug-induced CYPs [93].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 99%

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 addition to their role in nutrients absorption bile acids function as signaling hormones by activating a family of receptors that includes nuclear receptors such as the Farnesoid-x-receptor (FXR) [6], Constitutive Androstane Receptor (CAR), [7], Pregnane-x-receptor (PXR) [8], liver-x-receptor (LXR) [9] and the Vitamin D receptor (VDR), and G-protein coupled receptors (i.e. TGR5 or GPBAR1) [10,11].…”

Section: Research Papermentioning

confidence: 99%