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At least 19 recordsLinked to original sources
PubMed2006

International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor.

The nuclear receptors of the NR1H and NR1I subgroups include the constitutive androstane receptor, pregnane X receptor, farnesoid X receptors, liver X receptors, and vitamin D receptor. The newly emerging functions of these related receptors are under the control of metabolic pathways, including metabolism of xenobiotics, bile acids, cholesterol, and calcium. This review summarizes results of structural, pharmacologic, and genetic studies of these receptors.

Animals↗
PubMed2005

Evidence for an indirect transcriptional regulation of glucose-6-phosphatase gene expression by liver X receptors.

Liver X receptor (LXR) paralogues alpha and beta (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family and have oxysterols as endogenous ligands. LXR activation reduces hepatic glucose production in vivo through the inhibition of transcription of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase). In the present study, we investigated the molecular mechanisms involved in the regulation of G6Pase gene expression by LXR. Both T0901317, a synthetic LXR agonist, and the adenoviral overexpression of either LXRalpha or LXRbeta suppressed G6Pase gene expression in H4IIE hepatoma cells. However, compared to the suppression of G6Pase expression seen by insulin, the decrease of G6Pase mRNA by LXR activation was delayed and was blocked by cycloheximide, an inhibitor of protein synthesis. These observations, together with the absence of a conserved LXR-binding element within the G6Pase promoter, suggest an indirect inhibition of G6Pase gene expression by liver X receptors.

Animals↗
PubMed2003

Transcriptional regulation of farnesyl pyrophosphate synthase by liver X receptors.

Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are involved in cholesterol and lipid metabolism. In addition to liver, the brain is another site where LXRs may control cholesterol homeostasis. In the brain, the regulation of cholesterol homeostasis is independent from other parts of the body, and its disturbance is associated with neurodegenerative disorders, such as Alzheimer's disease. We have used PCR-based suppressive subtractive cloning to identify new LXR target genes in brain cells. In this report, we show that farnesyl pyrophosphate synthase (FPPS) is a new target gene for LXR in astrocytes and neurons. Farnesyl pyrophosphate is an obligate intermediate for de novo cholesterol synthesis and a substrate for protein farnesylation. Stimulation of FPPS mRNA synthesis by an LXR agonist, Hypocholamide, was observed in several cell lines from the central nervous system. We identified a single putative direct repeat 4 (DR4) LXR response element in the FPPS promoter. In a reporter gene assay, LXR transactivated a reporter gene bearing a truncated FPPS promoter containing this DR4 cis-element but not if the DR4 element was mutated. Using gel-mobility shift assay, we further demonstrated the direct interaction between the LXR/retinoid X receptor (RXR) heterodimer and the response element. Taken together, our results indicate that LXRs directly regulate FPPS gene expression, and thus may play a role in modulating cholesterol synthesis in the brain.

Alkyl and Aryl Transferases↗
PubMed2005

Selection of DNA aptamers against rat liver X receptors.

Liver X receptors alpha and beta (LXRalpha; LXRbeta) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. LXRs play an important role in the reverse cholesterol transport and govern the expression of many of the proteins that are indispensable for the regulation of normal cholesterol levels in the body. SELEX, an in vitro selection technology, was used on a single stranded DNA library harboring a 12 randomized nucleotide sequence in order to isolate aptamers showing affinity for LXRalpha. Enzyme-linked assays and surface plasmon resonance measurements showed that the selected aptamers had strong affinities for LXRalpha with apparent dissociation constants, K(d)s, in nanomolar range. All clones carried CG-repeats, indicating a probability for a similar manner of binding to LXRalpha. Very high cross-reactivities were observed when testing the aptamers with LXRbeta (up to 700%) and RXRalpha (up to 50%). If instead we regard the aptamer sequences as selected against LXRbeta, the cross-reactivities decrease considerably, to 17% for LXRalpha and 7% for RXRalpha. Therefore, in the future we are planning to use the obtained aptamers as binders for LXRbeta.

Animals↗
PubMed2004

Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor.

Liver X receptors (LXRs) play key roles in the regulation of cholesterol homeostasis by limiting cholesterol accumulation in macrophages within arterial wall lesion sites by a mechanism that includes the upregulation of ATP binding cassette transporters. These atheroprotective properties distinguish LXRs as potential targets for pharmaceutical intervention in cardiovascular disease. Their associated activity for promoting lipogenesis and triglyceride accretion through the activation of sterol-response element binding protein 1c (SREBP-1c) expression, however, represents a potential proatherogenic liability. A newly characterized synthetic oxysterol, N,N-dimethyl-3beta-hydroxycholenamide (DMHCA), represents a gene-selective LXR modulator that mediates potent transcriptional activation of ABCA1 gene expression while exhibiting minimal effects on SREBP-1c both in vitro and in vivo in mice. DMHCA has the potential to stimulate cholesterol transport through the upregulation of LXR target genes, including ABCA1, in liver, small intestine, and peritoneal macrophages. Compared with known nonsteroidal LXR agonists, however, DMHCA exhibits only limited activity for increasing hepatic SREBP-1c mRNA and does not alter circulating plasma triglycerides. Cell-based studies also indicate that DMHCA enhances cholesterol efflux in macrophages and suggest a mechanism whereby this selective modulator can potentially inhibit cholesterol accumulation. DMHCA and related gene-selective ligands of LXR may have application to the study and treatment of atherosclerosis.

ATP Binding Cassette Transporter 1↗
PubMed2004

Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor alpha, retinoid X receptor, and liver X receptor in mouse liver.

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor alpha (PPARalpha) and liver X receptor (LXR) through regulation of genes involved in fatty acid and cholesterol metabolism. Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPARalpha, and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these nuclear receptors, transcript profiles were generated from the livers of wild-type and PPARalpha-null mice exposed to the RXR pan-agonist 3,7-dimethyl-6S,7S-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]-2E,4E-heptadienoic acid (AGN194,204) or the PPAR pan-agonist WY-14,643 (WY; pirinixic acid) and compared with the profiles from the livers of wild-type and LXRalpha/LXRbeta-null mice after exposure to the LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)phenyl] sulfonamide (T0901317). All 218 WY-regulated genes altered in wild-type mice required PPARalpha. Remarkably, approximately 80% of genes regulated by AGN194,204 required PPARalpha including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPARalpha-dependent and -independent components. Overlaps of approximately 31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPARalpha and LXRalpha/LXRbeta for statistical significance. Ofthe 50 overlapping genes regulated by T0901317 and WY, all but one were regulated in a similar direction. These results 1) identify new transcriptional targets of PPARalpha and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPARalpha in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPARalpha-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.

Animals↗
PubMed2006

Cholesterol-sensing receptors, liver X receptor alpha and beta, have novel and distinct roles in osteoclast differentiation and activation.

UNLABELLED: The liver X receptor (alpha,beta) is responsible for regulating cholesterol homeostasis in cells. However, our studies using the LXRalpha-/-, LXRbeta-/-, and LXRalpha-/-beta-/- mice show that both LXRalpha and beta are also important for bone turnover, mainly by regulating osteoclast differentiation/activity. INTRODUCTION: The liver X receptors (alpha,beta) are primarily responsible for regulating cholesterol homeostasis within cells and the whole body. However, as recent studies show that the role for this receptor is expanding, we studied whether the LXRs could be implicated in bone homeostasis and development. MATERIALS AND METHODS: pQCT was performed on both male and female LXRalpha-/-, LXRbeta-/-, LXRalpha-/-beta-/-, and WT mice at 4 months and 1 year of age. Four-month-old female mice were additionally analyzed with reference to qPCR, immunohistochemistry, histomorphometry, transmission electron microscopy, and serum bone turnover markers. RESULTS: At the mRNA level, LXRbeta was more highly expressed than LXRalpha in both whole long bones and differentiating osteoblast-like MC3T3-E1 and osteoclast-like RAW 264.7 cells. Four-month-old female LXRalpha-/- mice had a significant increase in BMD because of an increase in all cortical parameters. No difference was seen regarding trabecular BMD. Quantitative histomorphometry showed that these mice had significantly more endosteal osteoclasts in the cortical bone; however, these cells appeared less active than normal cells as suggested by a significant reduction in serum levels of cross-linked carboxyterminal telopeptides of type I collagen (CTX) and a reduction in bone TRACP activity. Conversely, the female LXRbeta-/- mice exhibited no change in BMD, presumably because a significant decline in the number of the trabecular osteoclasts was compensated for by an increase in the expression of the osteoclast markers cathepsin K and TRACP. These mice also had a significant decrease in serum CTX, suggesting decreased bone resorption; however, in addition presented with an increase in the expression of osteoblast associated genes, bone formation markers, and serum leptin levels. CONCLUSIONS: Our findings show that both LXRs influence cellular function within the bone, with LXRalpha having an impact on osteoclast activity, primarily in cortical bone, whereas LXRbeta modulates trabecular bone turnover.

Acid Phosphatase↗
PubMed2003

A natural product ligand of the oxysterol receptor, liver X receptor.

Natural products have been identified as ligands for a number of members of the nuclear hormone receptor (NHR) superfamily. Often these natural products are used as dietary supplements to treat myriad ailments ranging from perimenopausal hot flashes to hypercholesterolemia and reduced cognitive function. Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St. John's wort (pregnane X receptor, NR1I2). In this study, we identified the first nonoxysterol natural product that functions as a ligand for the liver X receptor (LXRalpha and LXRbeta; NR1H3, NR1H2), a NHR that acts as the receptor for oxysterols and plays a key role in regulation of cholesterol metabolism and transport as well as glucose metabolism. We show that paxilline, a fungal metabolite, is an efficacious agonist of both LXRalpha and LXRbeta in biochemical and in vitro cell-based assays. Paxilline binds directly to both receptors and is an activator of LXR-dependent transcription in cell-based reporter assays. We also demonstrate that paxilline binding to the receptors results in efficient activation of transcription of two physiological LXR target genes, ABCA1 and SREBP. The discovery of paxilline, the first reported nonoxysterol natural product ligand of the LXRs, may provide insight into the mechanism of ligand recognition by these receptors and reaffirms the utility of examining natural product libraries for identifying novel NHR ligands.

ATP Binding Cassette Transporter 1↗
PubMed2005

Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor.

Oxysterols are intermediates in the synthesis of bile acids and steroid hormones from cholesterol and function as ligands for liver X receptor (LXR). Bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids and is tightly regulated by its substrates bile acids through nuclear receptor farnesoid X receptor (FXR). In a microarray study using human hepatocytes, BSEP was markedly induced not only by chenodeoxycholic acid (CDCA) but also by oxysterol 22(R)-hydroxycholesterol [22(R)-OHC]. We hypothesized that the expression of BSEP was induced by oxysterols through activation of LXR. To test the hypothesis, human primary hepatocytes or hepatoma cells were treated with 22(R)-OHC, and expression of BSEP was determined. The level of BSEP mRNA was increased as much as 5-fold upon oxysterol induction. In contrast to our hypothesis, the oxysterol-induced up-regulation of BSEP is mediated through FXR but not LXR. BSEP promoter activity was markedly induced by 22(R)-OHC in the presence of FXR but not LXRs. Mutation of the FXR element IR1 in the BSEP promoter significantly reduced its ability to respond to oxysterol induction. To determine whether 22(R)-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. Mutation of residues R331 and I352 abolished activation mediated by CDCA and 22(R)-OHC. In contrast, substitution of residues L340 and R351 differentiated CDCA- and 22(R)-OHC-mediated activation. In conclusion, oxysterol 22(R)-OHC functions as an FXR ligand to induce BSEP expression and differs in the binding with FXR from CDCA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha.

In rodent liver, transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the rate-limiting step in the classic bile acid synthetic pathway, is stimulated by the liver X receptor alpha (LXRalpha), a nuclear receptor for oxysterol metabolites of cholesterol. This feed-forward regulatory loop provides a mechanism for the elimination of excess cholesterol from the body. In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXRalpha has the opposite effect, repressing CYP7A1 expression. This repression is mediated, at least in part, through induction of the orphan nuclear receptor, short heterodimer partner (SHP), which is also induced by bile acids. We demonstrate that SHP is regulated directly by LXRalpha through a DNA response element that overlaps with the previously characterized bile acid response element. Our data reveal a fundamental difference in the regulation of CYP7A1 in rodent and human hepatocytes and provide evidence that different species employ distinct molecular strategies to regulate cholesterol homeostasis.

Animals↗
PubMed2005

Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator-activated receptor {gamma}-liver X receptor {alpha}-ABCA1 pathway.

It is widely accepted that stimulation of reverse cholesterol transport, the efflux of excess cholesterol from peripheral tissues and transferring it to the liver for biliary excretion, is becoming an important component in reducing excess cholesterol deposition in atherosclerotic plaques. The ATP-binding cassette transporter has been identified as a key regulator of macrophage cholesterol efflux and apoAI-mediated reverse cholesterol transport. In vivo studies have documented anthocyanins, a large group of naturally phenolic compounds rich in plants, possess substantial capacities in improving plasma cholesterol levels. In this study, we investigated the potential role of anthocyanins in modulating cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and the possible molecular mechanism linking ABCA1 to cholesterol efflux. Incubation of the mouse peritoneal macrophages and macrophage-derived foam cells with cyanidin-3-O-beta-glucoside and peonidin-3-O-beta-glucoside led to dose-dependent (1-100 microM) induction in cholesterol efflux and ABCA1 mRNA expression, and this effect could be blocked by the ABCA1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, disodium salt, and a general inhibitor of gene transcription actinomycin D. Treatment of the macrophages with anthocyanins also activated peroxisome proliferator-activated receptor gamma, liver X receptor alpha mRNA expression, and their mediated gene expression. Addition of geranylgeranyl pyrophosphate ammonium salt or GW9662 markedly inhibited the anthocyanin-induced increase of ABCA1 gene expression and apoAI-mediated cholesterol efflux. These data demonstrated that anthocyanin induces cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and that stimulation of cholesterol efflux by anthocyanin is mediated, at least in part, by peroxisome proliferator-activated receptor gamma-liver X receptor alpha-ABCA1 signaling pathway activation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

The liver X receptors.

The liver X receptors (LXRs), members of the nuclear receptor superfamily, are potential targets for a variety of diseases. While there are many opportunities for the development of LXR-based therapeutics, there are some major hurdles, such as the ability of LXRs to cause hypertriglyceridemia, as well as some species-dependent aspects of LXR-mediated gene regulation. In addition to classical pharmacological approaches using relevant cellular and animal models, systematic molecular-based strategies will be important in overcoming these obstacles.

Alzheimer Disease↗
PubMed2005

Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand.

Liver X receptors (LXR) have been implicated in cholesterol homeostasis. Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of the bark and stem extract of Garcinia humilis led to the discovery of a new polyisoprenylated benzophenone named guttiferone I (1). The IC(50) value for this compound in the LXRalpha-SPA binding assay was 3.4 muM. Details of the isolation, structure elucidation, and ligand binding activity of 1 are described.

Benzophenones↗
PubMed2005

Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway.

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism and are also involved in glucose metabolism. However, the functional role of LXRs in human skeletal muscle is at present unknown. This study demonstrates that chronic ligand activation of LXRs by a synthetic LXR agonist increases the uptake, distribution into complex cellular lipids, and oxidation of palmitate as well as the uptake and oxidation of glucose in cultured human skeletal muscle cells. Furthermore, the effect of the LXR agonist was additive to acute effects of insulin on palmitate uptake and metabolism. Consistently, activation of LXRs induced the expression of relevant genes: fatty acid translocase (CD36/FAT), glucose transporters (GLUT1 and -4), sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor-gamma, carnitine palmitoyltransferase-1, and uncoupling protein 2 and 3. Interestingly, in response to activation of LXRs, myotubes from patients with type 2 diabetes showed an elevated uptake and incorporation of palmitate into complex lipids but an absence of palmitate oxidation to CO(2). These results provide evidence for a functional role of LXRs in both lipid and glucose metabolism and energy uncoupling in human myotubes. Furthermore, these data suggest that increased intramyocellular lipid content in type 2 diabetic patients may involve an altered response to activation of components in the LXR pathway.

Anticholesteremic Agents↗
PubMed2006

Phosphorylation of the liver X receptors.

The liver X receptors (LXRs) function as nutritional sensors for cholesterol and have important roles in lipid metabolism, glucose homeostasis, and inflammation. We provide the first evidence that LXRs are phosphorylated proteins. Mutational analysis and metabolic labeling indicate LXRalpha is phosphorylated on serine 198 in the hinge region. This is a consensus target for the MAPK family. A phosphorylation-deficient mutant, LXRalpha S198A, remains nuclear and responds to ligands like the wild-type protein. The biological significance of LXR phosphorylation remains to be elucidated but could provide a novel mechanism for the regulation of LXR signaling pathways and cellular metabolism.

Animals↗
PubMed2004

Role of p160 coactivator complex in the activation of liver X receptor.

OBJECTIVE: Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer. METHODS AND RESULTS: Overexpression of LXRalpha, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner. CONCLUSIONS: The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.

ATP Binding Cassette Transporter 1↗
PubMed2002

Effects of fatty acids on gene expression: role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c.

Dietary fatty acids have numerous effects on cellular function, many of which are achieved by altering the expression of genes. The present paper reviews recent data on the mechanisms by which fatty acids influence DNA transcription, and focus specifically on the importance of three transcription factors: peroxisome proliferator-activated receptor alpha; liver X receptor alpha; sterol regulatory element-binding protein 1c. These data indicate that fatty acids induce or inhibit the mRNA expression of a variety of different genes by acting both as agonists and as antagonists for nuclear hormone receptors.

Animals↗
PubMed2004

Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages.

Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.

Animals↗