Disease relevance of NR1H3

• In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXRalpha [1].
• Obesity and NIDDM were not associated with change in PPARs and LXR alpha expression in adipose tissue [2].
• Moreover, the LDLR promoter contained an LXR response element that was recognized by LXRalpha/RXRalpha (retinoid X receptor alpha) heterodimers in hepatoblastoma cells [3].
• Conversely in acute myeloid leukemia (AML), a heterogeneous expression pattern was found consisting of a considerably higher expression of particularly LXR-alpha in CD34(+) cells and a reverse expression pattern in a subset of AML CD34(+)CD38(+) cells [4].
• Murine J774.2 macrophages were stimulated with Escherichia coli lipopolysaccharide (concentration, 10 microg/mL) with or without the PPARgamma ligand, 15-deoxy-Delta prostaglandin J2 (15d-PGJ2), or the LXRalpha ligands, 22(R)-hydroxycholesterol and T0901317 (concentration range, 0.01-10 micromol/L), alone or in combination [5].

High impact information on NR1H3

• These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription [6].
• In addition, LXR alpha increases cholesterol synthesis and release of nonesterified fatty acids [7].
• Finally, treatment of mice with an LXR alpha agonist results in increased serum levels of glycerol and nonesterified fatty acids, consistent with increased lipolysis within adipose tissue [7].
• Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor alpha in adipocyte metabolism [7].
• We demonstrate here that autoregulation of the LXR alpha gene is an important component of this lipid-inducible efflux pathway in human macrophages [8].

Chemical compound and disease context of NR1H3

• In conclusion, these observations establish LXRalpha as a crucial regulator of bile acid glucuronidation in humans and suggest that accumulation of oxysterols in hepatocytes during cholestasis favors bile acid detoxification as glucuronide conjugates [9].

Biological context of NR1H3

• Using a quantitative and sensitive reverse transcription (RT)-competitive polymerase chain reaction (PCR) assay, we determined the distribution and relative mRNA expression of the four PPARs (alpha,beta, gamma1, and gamma2) and liver X receptor-alpha (LXR alpha) in the main tissues implicated in lipid metabolism [2].
• Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients [2].
• Unliganded thyroid hormone receptor-beta1 represses liver X receptor alpha/oxysterol-dependent transactivation [10].
• RESULTS: ABCA1 and LXRalpha gene expression were significantly elevated in atherosclerotic plaques (P<0.0001 and 0.03, respectively) [11].
• Despite significant upregulation of ABCA1 mRNA, possibly mediated via LXRalpha, ABCA1 protein is markedly reduced in advanced carotid atherosclerotic lesions [11].

Anatomical context of NR1H3

• PPAR alpha and LXR alpha were mainly expressed in liver, while PPAR gamma1 predominated in adipose tissue and large intestine [2].
• PPARalpha, PPARbeta, PPARgamma and LXRalpha protein were detected in nuclear extracts of sebaceous glands [12].
• In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXRalpha has the opposite effect, repressing CYP7A1 expression [13].
• Treatment of mature adipocytes with t10,c12 CLA alone or in combination with Darglitazone down-regulates the mRNA expression of PPARgamma as well as its target genes, fatty acid binding protein (aP2) and liver X receptor alpha (LXRalpha) [14].
• Thus, our data suggest that PPARgamma and LXRalpha may interact in controlling the inflammatory response in macrophages [5].

Associations of NR1H3 with chemical compounds

• Together with its isoform LXRalpha (NR1H3) it regulates target genes involved in metabolism and transport of cholesterol and fatty acids [15].
• We found that TEPA, but not EPA, decreased the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), which is a coactivator of both LXRalpha and SREBP-1 [16].
• In this study, we compared the effects of trans geometric isomers of eicosapentaenoic acid (TEPA) on triacylglycerol synthesis induced by a synthetic LXRalpha agonist (T0901317) with the effects of EPA in HepG2 cells [16].
• Dietary PUFAs, especially eicosapentaenoic acid (EPA) in marine oils, improve serum lipid profiles by suppressing liver X receptor alpha (LXRalpha) activity in the liver [16].
• In addition, NO-1886 upregulated liver X receptor alpha and affected the expression of scavenger receptor class B type I in the liver [17].

Physical interactions of NR1H3

• The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity [18].

Regulatory relationships of NR1H3

• 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 [3].
• In the liver, the liver X receptor alpha induces the cholesterol 7alpha-hydroxylase (CYP7A1) gene, which controls the rate-limiting step in bile acid synthesis, the major cholesterol excretion pathway [19].
• We demonstrate that SHP is regulated directly by LXRalpha through a DNA response element that overlaps with the previously characterized bile acid response element [13].
• For example, the expression of the genes encoding the adiponectin receptors may be regulated by liver X receptor alpha [20].
• Expression of antisense TRRAP RNA in HepG2 cells abolished the ligand-induced expression of LXRalpha target genes [21].

Other interactions of NR1H3

• The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2) [22].
• The increased mRNA levels of ABCA1 and LXRalpha were correlated in atherosclerotic tissue (r=0.85; P<0.0001) [11].
• IL-10 effects were also studied in cells transfected with liver X receptor alpha (LXRalpha)-siRNA or a LXRalpha response element (LXRE) reporter construct [23].
• We established ABCA1 and LXRalpha gene expression by real-time quantitative polymerase chain reaction in 10 control and 18 atherosclerotic specimens [11].
• Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha [13].

Analytical, diagnostic and therapeutic context of NR1H3

• In this report, we show that these orally administered LXRalpha agonists have an overall hypolipidemic effect in hypercholesterolemic rats, mice and hamsters, which indicates that in these animal models, endogenous LXRalpha agonist is a limiting factor for induction of cholesterol disposal [24].
• Immunoprecipitation experiments revealed that PPARgamma interacted with LXRalpha [5].
• Furthermore, there was evidence of interaction between LXRA and LXRB alleles in determining body mass index [25].
• In situ hybridization and RT-PCR assays further indicated that LXRalpha mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli [26].
• In cultured rabbit mesangial cells, LXRalpha mRNA and protein were detected by RT-PCR and immunoblotting [26].

References