Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. There are two LXR isoforms termed alpha and beta which upon activation form heterodimers with retinoid X receptor and bind to LXR response element found in the promoter region of the target genes.
Liver X receptors (LXRs) are nuclear hormone receptors that act as oxysterol sensors, regulating genes involved in cholesterol and lipid metabolism. Elevated cholesterol levels can lead to enhanced oxysterol production and the activation of LXRs, which increase the gene expression (transactivation) of a number of target genes. Liver X receptors (LXR) are also ligand activated transcription factors belonging to the nuclear receptor super family. On binding with their ligands they form dimers with RXR and bind to LXR response elements (LXREs) on the promoters of their target genes and increase their expression.
There are two isoforms of LXR: α (NR1H3) and β (NR1H2). They were known as sterol sensors that regulate cholesterol and lipid metabolism and homeostasis. Oxysterols generated as a result of cholesterol metabolism, for example 22(R)-hydoxycholesterol, can act as natural ligands for these nuclear receptors. In the liver these have been shown to regulate the ABC family of cholesterol transporters and hepatic cytochrome P450 7A1 (CYP7A1) which catalyzes the conversion of cholesterol to bile acids. LXRα is highly expressed in the liver, but its expression is also found in adipose tissues, intestine, macrophages, lung and kidney. LXRβ is expressed ubiquitously.
LXRs possess diverse functions, ranging from cholesterol efflux to lipogenesis and anti-inflammation. LXRs have also been shown to exert anti-inflammatory properties by suppressing genes involved in inflammation, such as tumor necrosis factor alpha (TNFα), interleukins (IL-1β, IL-6), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NFκB) in murine macrophages. For this reasons, LXRs have been explored as a therapeutic target for atherosclerosis, diabetics, and Alzheimer's disease in animal models. In macrophages, LXRs play an important role in innate immunity and inflammatory signaling. LXR agonists enhance macrophage survival during bacterial infection. Activation of LXRs in liver also leads to induction of genes directly involved in lipid synthesis, such as sterol regulatory element-binding protein-1c (SREBP1c), fatty acid synthase (FAS) and stearoyl CoA desaturase (SCD). Chronic LXR activation in liver can cause hypertriglyceridemia and hepatosteatosis.
The immunomodulatory effects of LXRs rely on the association of LXRs with corepressor complexes bound to transcription factors, such as NFκB, that modulate the expression of inflammatory genes (transrepression). An additional therapeutic indication for LXRs is in Alzheimer’s disease (AD). LXR activation has been shown to increase the levels of the Apolipoprotein E (ApoE) in murine and human macrophages and in rat brain, where increased ApoE has been positively associated with amyloid Aβ clearance in AD models.
Since LXRs negatively regulate steroidogenesis, it is possible that these high levels in preovulatory granulosa cells may prevent premature luteinization. Progesterone is clearly a key regulator of periovulatory events and rapid synthesis is therefore essential. Given the activity of HSD3B in non-luteinized primate granulosa cells, it is hypothesized that these cells are capable of progesterone synthesis but lack free cholesterol. Thus LXRs may play a heretofore undescribed role in preventing premature luteinization and allow optimum maturation of the developing follicle prior to ovulation. Liver X receptors in the preovulatory follicle are hypothesized to suppress steroidogenesis through at least two distinct mechanisms. The first is through an efflux of cholesterol. The second mechanism is through the repression of key steroidogenic factors and lipoprotein receptor expression.
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Lee, Jung Hoon. The role of the aryl hydrocarbon receptor and the liver X receptor in gene regulation and metabolic homeostasis. Diss. University of Pittsburgh, 2009.
Noto, Paul Bart. Analysis of Liver X Receptor target gene expression across species. Drexel University, 2013.