Alternative titles; symbols
HGNC Approved Gene Symbol: NR1H3
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:47,248,300-47,269,033 (from NCBI)
The liver X receptors, LXRA and LXRB (NR1H2; 600380), form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRA is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRB is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs; see 180245) and regulate expression of target genes containing LXR response elements (summary by Korf et al., 2009).
Retinoic acid mediates tissue-specific expression of target genes through its binding to nuclear hormone receptors (e.g., RARA; 180240). To activate transcription, these receptors bind specific sites, called hormone response elements, within the target gene's regulatory region. By screening a human liver cDNA library with an RARA cDNA probe, Willy et al. (1995) identified a cDNA encoding NR1H3, or LXRA, an orphan member of the nuclear receptor superfamily. The predicted 447-amino acid LXRA protein contains a DNA-binding domain and a putative ligand-binding domain; the amino acid sequences of these domains are 77% identical to those of NR1H2. Northern blot analysis showed strong expression of a 1.9-kb LXRA transcript in metabolic organs such as liver, kidney, and intestine. In mouse, Northern blot analysis detected a low level of Lxra expression at embryonic day 13.5 that continued to increase through parturition.
Willy et al. (1995) identified a distinct retinoid response element for LXRA/RXRA (180245) heterodimers, termed the LXR-responsive element (LXRE), that consists of 2 degenerate copies of the consensus hexad sequence spaced by 4 nucleotides. LXRA specifically interacted with RXRA in vivo to form a functional heterodimer in which RXRA was the ligand-binding subunit. Willy et al. (1995) found that LXRA-mediated gene activation was only induced by certain retinoids, including 9-cis retinoic acid (9cRA). They concluded that LXRA is a tissue-specific cofactor that permits RXRA to function as a potent 9cRA receptor with a distinct target gene specificity. Willy et al. (1995) stated that LXRA defines a novel retinoid response system.
In an elegant series of experiments designed to understand the effect of RXR activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor, FXR (603826), are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1 (ABCA1; 600046), and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
LXR activity is critical for physiologic lipid metabolism and transport. Tangirala et al. (2002) linked LXR signaling pathways to the pathogenesis of cardiovascular disease. Bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. The results demonstrated that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimicked many aspects of Tangier disease (205400), a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identified LXRs as targets for therapeutic intervention in cardiovascular disease.
Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression. In studies in cultured cells and in mice, Joseph et al. (2003) demonstrated that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages revealed reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibited the expression of inflammatory mediators such as inducible nitric oxide synthase (163730), cyclooxygenase (COX)-2 (600262), and interleukin-6 (IL6; 147620) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduced inflammation in a model of contact dermatitis and inhibited inflammatory gene expression in the aortas of atherosclerotic mice. These findings indicated that LXRs are lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
Mitro et al. (2007) showed that glucose binds and stimulates the transcriptional activity of LXR, a nuclear receptor that coordinates hepatic lipid metabolism. D-glucose and D-glucose-6-phosphate are direct agonists of both LXR-alpha and LXR-beta. Glucose activated LXR at physiologic concentrations expected in the liver and induced expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression were upregulated in liver and intestine of fasted mice refed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Mitro et al. (2007) concluded that their results identified LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.
Zelcer et al. (2009) demonstrated that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of LDL uptake. LXR inhibits the LDL receptor (LDLR; 606945) pathway through the transcriptional induction of IDOL (MYLIP; 610082), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduced, whereas LXR knockout increased, LDLR protein levels in vivo in a tissue-selective manner. IDOL knockdown in hepatocytes increased LDLR protein levels and promoted LDL uptake. Conversely, Zelcer et al. (2009) found that adenovirus-mediated expression of IDOL in mouse liver promoted LDLR degradation and elevated plasma LDL levels. Zelcer et al. (2009) concluded that the LXR-IDOL-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.
Using Lxra and Lxrb double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 (SREBF1; 184756) was recruited to the E-box element on the Il17 (603149) promoter upon Lxr activation and interacted with Ahr (600253) to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.
Hypercholesterolemia is a risk factor for estrogen receptor (ER; 133430)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Nelson et al. (2013) showed that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and LXR ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 (606530) and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, Nelson et al. (2013) concluded that lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.
Martinez et al. (2014) developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. These mice developed obesity and glucose intolerance with aging. Strikingly, offspring of male IUGR mice also developed glucose intolerance. Martinez et al. (2014) showed that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5-prime-UTR. Martinez et al. (2014) found the same epigenetic signature in the sperm of their progenitors, F1 males. Martinez et al. (2014) concluded that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring.
Peet et al. (1998) demonstrated that mice lacking the oxysterol receptor LXRA lost their ability to respond normally to dietary cholesterol and were unable to tolerate any amount of cholesterol in excess of that which they synthesized de novo. When fed diets containing cholesterol, Lxra -/- mice failed to induce transcription of the gene encoding cholesterol 7-alpha-hydroxylase (CYP7A1; 118455), the rate-limiting enzyme in bile acid synthesis. This defect was associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually led to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes was also altered in Lxra -/- mice. The results of Peet et al. (1998) demonstrated the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and established the role of LXRA as the major sensor of dietary cholesterol.
Repa et al. (2002) presented evidence for the direct control of the ATP-binding cassette sterol transporters Abca1 (600046), Abcg5 (605459), and Abcg8 (605460) by the liver X receptors. The intensity of hepatic and jejunal staining for Abcg5/g8 and Abca1 was increased in normal mice fed cholesterol or other Lxr agonists. Cholesterol feeding resulted in upregulation of Abcg5 and Abcg8 in the Lxrb-null mice, but not in the Lxra-null or double knockout mice, suggesting that Lxra is required for sterol upregulation of Abcg5/g8 in this model. In a rat hepatoma cell line, Lxr-dependent transcription of the Abcg5/g8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by the liver X receptors.
Joseph et al. (2002) demonstrated that the nonsteroidal Lxr agonist GW3965 has potent antiatherogenic activity in 2 different murine models: Ldlr -/- mice (606945) and ApoE -/- mice (107741).
Joseph et al. (2003) demonstrated that LXR agonists reduced inflammation in a model of contact dermatitis and inhibited inflammatory gene expression in the aortas of atherosclerotic mice; these and other findings suggested that LXRs are lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
In Abcg5/Abcg8-deficient mice, Yang et al. (2004) demonstrated that accumulation of plant sterols perturbed cholesterol homeostasis in the adrenal gland, with a 91% reduction in its cholesterol content. Despite very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. In cultured adrenal cells, stigmasterol but not sitosterol inhibited SREBP2 (600481) processing and reduced cholesterol synthesis; stigmasterol also activated the liver X receptor in a cell-based reporter assay. Yang et al. (2004) concluded that selected dietary plant sterols disrupt cholesterol homeostasis by affecting 2 critical regulatory pathways of lipid metabolism.
Macrophages play a direct role, through both innate and adaptive immunity, in microbial killing, and they orchestrate inflammatory responses through the release of immune modulators, such as chemokines and cytokines. Joseph et al. (2004) found that mice lacking both Lxra and Lxrb (Lxr-null) were highly susceptible to infection with Listeria monocytogenes (LM) in a dose-dependent manner. In addition, they determined that Lxra-deficient mice were more susceptible than Lxrb-deficient mice. Compared with wildtype mice, bacterial burdens were 2 logs higher in Lxr-null and Lxra -/- mice, and neutrophilic abscesses in liver were increased in Lxr-null mice. Analysis of plasma cytokine and chemokine mediators indicated no significant change in inflammatory mediators, except for Il6 and Il12p70 (see 161560). Microarray analysis and real-time RT-PCR revealed that the most striking difference in response to LM infection in the mutant mice was reduced expression of the antiapoptotic factor Sp-alpha (CD5L; 602592) and, to a lesser extent, Marco (604870), both of which are members of the scavenger receptor cysteine-rich repeat family. Sp-alpha expression was severely compromised in response to LXR ligands in Lxra -/- macrophages, but not in Lxrb -/- macrophages, and the Sp-alpha promoter was preferentially activated by Lxra. In contrast, expression of Cd14 (158120) and Cd68 (153634) increased in Lxr-null mice after LM infection. Infection of macrophages with LM or Shigella, but not with extracellular bacteria, strongly induced Lxra expression, but not Lxrb expression, via the NOD (see CARD4; 605980) signaling pathway. Flow cytometric and TUNEL analyses demonstrated increased apoptosis in Lxr-null macrophages compared with wildtype macrophages. Joseph et al. (2004) concluded that LXR activity and its regulation of Sp-alpha promotes macrophage survival and antimicrobial function in the setting of LM and intracellular pathogen infection.
In a mouse renin (179820)-expressing cell line, Morello et al. (2005) demonstrated that both LXRA and LXRB could bind to the renin promoter and regulate renin transcription; cAMP increased LXRA activity but decreased that of LXRB. In the mouse kidney, in situ hybridization studies showed colocalization of renin and LXRA in juxtaglomerular cells, and in mouse models, renin-angiotensin (see 106150) activation was associated with increased binding of LXRA to the renin promoter. In Lxra-null mice, the elevation of renin triggered by adrenergic stimulation was abolished; untreated Lxrb-null mice exhibited reduced kidney renin mRNA levels compared with controls. Lxra/Lxrb-null mice showed a combined phenotype of lower basal renin and blunted adrenergic response. Morello et al. (2005) concluded that LXRA and LXRB regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRA signaling pathway is required for adrenergic control of the renin-angiotensin system.
Cummins et al. (2006) demonstrated that under chronic dietary stress the adrenal glands of Lxra/Lxrb double-null mice accumulated free cholesterol, whereas wildtype mice maintained cholesterol homeostasis. At baseline, Lxra/Lxrb double-null mice exhibited a marked decrease in Abca1 and derepression of Star (600617) expression, causing a net decrease in cholesterol efflux and an increase in steroidogenesis. In Lxra/Lxrb double-null mice pretreated with dexamethasone to prevent the acute stress response, the phenotype of hypercorticosteronemia, cholesterol ester accumulation, and adrenomegaly was specific to loss of Lxra and not Lxrb. Western blot analysis showed increased expression of STAR in human and mouse adrenal cells treated with LXR and RXR agonists. Stimulation of Star expression by Lxra activation was mediated by binding of the Lxra/Rxra heterodimer to an LXR response element (LRE) in the mouse Star promoter. Cummins et al. (2006) suggested that LXRA provides a safety valve to limit free cholesterol levels as a basal protective mechanism in the adrenal gland.
Bradley et al. (2007) generated Lxra-null/Apoe-null mice and observed extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis, which suggested that the level of Lxr pathway activation in macrophages achieved by Lxrb and endogenous ligand was unable to maintain homeostasis in the setting of hypercholesterolemia. Treatment of Lxra-null/Apoe-null mice with the highly efficacious synthetic Lxr agonist GW3965, however, ameliorated the cholesterol overload phenotype and reduced atherosclerosis. Bradley et al. (2007) concluded that LXRA has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia.
Using mice lacking Lxra or Lxrb, Bensinger et al. (2008) showed that T-cell activation triggered induction of the oxysterol-metabolizing enzyme Sult2b1 (604125), suppression of the Lxr pathway for cholesterol transport, and promotion of the Srebp2 pathway for cholesterol synthesis. Proliferation was inhibited by Lxr ligation during T-cell activation by mitogen, but cells from mice lacking Lxrb had a proliferative advantage. Lymphocytes lacking Abcg1 (603076) were not inhibited in the presence of Lxr agonists, indicating that transport of sterols by ABCG1 is required for LXR agonist-mediated inhibition. Mice lacking Lxrb displayed lymphoid hyperplasia and enhanced responses to antigenic challenge. Bensinger et al. (2008) concluded that cellular cholesterol levels in dividing T cells are maintained, in part, through reciprocal regulation of LXR and SREBP transcriptional programs, and that LXR signaling is a metabolic checkpoint that modulates cell proliferation and immunity.
Using RT-PCR analysis of Cd11c (ITGAX; 151510)-positive lung and alveolar cells from mice infected intratracheally with Mycobacterium tuberculosis, Korf et al. (2009) detected increased expression of Lxra and Lxrb and their target genes, Apoe and Abca1, as well as Pparg (601487) and Srebp1. Mice deficient in Lxra or both Lxra and Lxrb, but not mice deficient in Lxrb only, were more susceptible to infection than wildtype mice in terms of bacterial burden and in size and number of granulomatous lesions. Double-knockout mice failed to mount an early neutrophilic response and showed dysregulation in the expression of inflammatory factors by Cd11c cells. Diminished Th1 and Th17 function, but not Th2 function, was also found in lungs of infected mice. Treatment with Lxr agonists resulted in a 10-fold decrease in bacterial burden and increased Th1 and Th17 function. Korf et al. (2009) concluded that the neutrophil-IL17 axis depends on LXR signaling and is important in resistance to M. tuberculosis infection.
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