Article

Identification of human low-density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha.

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
FEBS Letters (impact factor: 3.54). 10/2006; 580(20):4929-33. DOI:10.1016/j.febslet.2006.08.010 pp.4929-33
Source: PubMed

ABSTRACT Liver X receptor alpha (LXRalpha) is a member of the nuclear receptor superfamily that is activated by oxysterols, and plays a pivotal role in regulating the metabolism, transport and uptake of cholesterol. Here, we demonstrate that LXRalpha also regulates the low-density lipoprotein receptor (LDLR) gene, which mediates the endocytic uptake of LDL cholesterol in the liver. An LXR agonist induced the expression of LDLR in cultured hepatoblastoma cells. Moreover, the LDLR promoter contained an LXR response element that was recognized by LXRalpha/RXRalpha (retinoid X receptor alpha) heterodimers in hepatoblastoma cells. These results suggest a novel pathway whereby LXRalpha might modulate cholesterol metabolism.

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    Article: Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells.
    Elizabeth A DiBlasio-Smith, Maya Arai, Elaine M Quinet, Mark J Evans, Tad Kornaga, Michael D Basso, Liang Chen, Irene Feingold, Anita R Halpern, Qiang-Yuan Liu, Ponnal Nambi, Dawn Savio, Shuguang Wang, William M Mounts, Jennifer A Isler, Anna M Slager, Michael E Burczynski, Andrew J Dorner, Edward R LaVallie
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    ABSTRACT: LXRs (Liver X Receptor alpha and beta) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds. Blood markers of LXR agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators. Transcript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative reverse transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRalpha, LXRbeta, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated ex vivo with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623. A single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRalpha and LXRbeta, and all cell types significantly increased ABCA1 and ABCG1 expression upon ex vivo LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription. Peripheral blood cells express LXRalpha and LXRbeta, and respond to LXR agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.
    Journal of Translational Medicine 11/2008; 6:59. · 3.41 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

cholesterol
 
cultured hepatoblastoma cells
 
endocytic uptake
 
hepatoblastoma cells
 
LDL cholesterol
 
LDLR
 
LDLR promoter
 
Liver X receptor alpha
 
low-density lipoprotein receptor
 
LXR agonist induced
 
LXR response element
 
LXRalpha
 
LXRalpha/RXRalpha
 
mediates
 
novel pathway
 
oxysterols
 
regulating
 
retinoid X receptor alpha
 
uptake