Last Updated: September 11, 2024
Introduction to Liver X Receptor Family
The liver X receptors were originally cloned based upon their nucleotide sequence homology to other nuclear receptors. Originally designated as “orphan” receptors, because no naturally occurring ligands had been identified, they were later shown to bind cholesterol metabolites, termed oxysterols, which activated the receptors at physiological concentrations. Several cholesterol metabolites have been identified as being able to activate the LXRs such as 22(R)-hydroxycholesterol, 27-hydroxycholesterol, 24(S),25-epoxycholesterol, and 24(S)-hydroxycholesterol.
Humans express two LXR encoding genes, both of which are members of the nuclear hormone receptor family. These genes encode the LXRα and LXRβ isoforms. Both isoforms are highly related sharing 78% amino acid identity in their DNA-binding and ligand-binding domains.
The LXRα protein is encoded by the NR1H3 gene. The NR1H3 gene is located on chromosome 11p11.2 and is composed of 17 exons that generate six alternatively spliced mRNAs that collectively encode five distinct protein isoforms.
The LXRβ protein is encoded by the NR1H2 gene. The NR1H2 gene is located on chromosome 19q13.33 and is composed of 10 exons that generate two alternatively spliced mRNAs encoding proteins of 460 amino acids (isoform 1) and 363 amino acids (isoform 2).
Role of LXR in Lipid Metabolism
LXRα is highly expressed in tissues known to play important roles in overall lipid metabolism such as the liver, adipose tissue, small intestine, spleen, macrophages, and kidney. LXRβ is ubiquitously expressed. The LXRs form permissive heterodimers with the RXRs and as such can regulate gene expression either upon binding LXR ligands, such as oxysterols, or RXR ligands such as 9-cis-retinoic acid. The LXR/RXR heterodimers bind to LRX-responsive elements (LXRE) in target DNA that consists of direct repeats (DR) with the core sequence AGGTCA separated by 4 nucleotides (designated DR4). In the absence of ligand the LXR/RXR heterodimer resides in the nucleus bound to LXRE in a complex with transcriptional co-repressors such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor co-repressor (N-CoR). Upon ligand binding there is a conformational change in the complex that facilitates a co-repressor for co-activator complex exchange and transcriptional activation of target genes.
Conclusive evidence regarding the regulation of and by the LXR was made possible by the use of LXR knock-out mice. In LXRα–/– mice there is marked cholesteryl ester accumulation when these mice are fed a cholesterol-rich diet. These initial studies resulted in the identification of cholesterol 7α-hydroxylase (CYP7A1), the rate limiting enzyme in bile acid synthesis, as the first known target of LXR. Because the LXR bind oxysterols they are important in the regulation of whole body cholesterol levels.
The function of LXR in the liver is to mediate cholesterol metabolism by inducing the expression of SREBP-1c. SREBP-1c is a transcription factor involved in the control of the expression of numerous genes including several involved in cholesterol synthesis. The LXR are also involved in the process of reverse cholesterol transport which is the process by which the lipoprotein particle, HDL, carries cholesterol from the peripheral tissues to the liver. For information of the process of reverse cholesterol transport visit the Lipoproteins, Blood Lipids, and Lipoprotein Metabolism page.
Activation of LXR in vivo using high-affinity synthetic ligands results in increased levels of plasma HDL and an increase in cholesterol excretion. The ability of LXR to exert these effects on cholesterol excretion is due to their ability to regulate the expression of members of the ATP-binding cassette (ABC) family of membrane transporters (see the Biological Membranes and Membrane Transport Processes page for more information on ABC transporters). The expression levels of ABCA1, ABCG5, and ABCG8 are all increased by activation of the LXR.
The ABCA1 transporter is involved in the efflux of cholesterol and phospholipids to lipid-poor lipoproteins. Deficiencies in ABCA1 are the cause of Tangier disease, a disorder characterized by an accumulation of cholesteryl esters in reticuloendothelial tissues (e.g. tonsils, lymph nodes, spleen, thymus, and bone marrow). In the liver, ABCA1 promotes the formation of pre-β HDL (a lipoprotein particle composed entirely of ApoA-I and phospholipids). This latter function of ABCA1 demonstrates its important role in hepatic production of HDL.
The role of LXs in reducing intestinal uptake of dietary cholesterol is mediated primarily via the induction of the ABCG5 and ABCG8 genes. The ABCG5 and ABCG8 proteins form an obligate heterodimer pair that function to limit plant sterol and cholesterol uptake by the gut and mediate cholesterol efflux from the liver into the bile. Mutations in either ABCG5 or ABCG8 result in a rare genetic disorder identified as sitosterolemia (also called phytosterolemia).
Role of LXR in Cholesterol Metabolism
The LXR also play an important role in overall cholesterol metabolism in macrophages. This role of LXR in macrophages is clinically important as the macrophage is a central cell in the development of atherosclerotic lesions. The role of macrophages in atherosclerosis stems from their ability to phagocytose oxidized and modified lipoproteins following which they release pro-inflammatory cytokines. When macrophages are present in the atherosclerotic lesion they are able to accumulate LXR ligands such as oxysterols from the oxidized lipoproteins.
Within macrophages the primary function of LXR is to maintain cholesterol homeostasis. When macrophages consume oxidized lipoproteins the LXR genes are activated by the oxysterols present which in turn results in the activation of the ABCA1 gene. Activation of ABCA1 in macrophages allows for increased efflux of cholesterol to HDL increasing the rate of reverse cholesterol transport.
Another ABC transporter activated in macrophages by LXRs is ABCG1. ABCG1 facilitates cholesterol efflux to HDL that do not contain apoA-I which distinguishes its activity from that of ABCA1. LXR also activate apoE gene expression in macrophages (but not in liver) as well as apoC-I, apoC-II, and apoC-IV. There is a clear correlation to the protective role of apoE in atherogenesis so impaired activation of this gene in macrophages likely plays a significant part in the development of atherosclerotic lesions. Indeed, in mouse models of atherosclerosis it has been shown that activation of LXR results in up to a 50% reduction in the size of lesions. Further proof of the anti-atherogenic potential of LXR has been demonstrated in mice in which there has been a macrophage-specific knock-out of the LXR. In these mice there is a marked increase in the size of atherosclerotic lesions.
Within the macrophage environment LXR not only influence cholesterol homeostasis but also directly impact the processes of macrophage inflammatory signaling. Within the atherosclerotic lesion the inflammatory processes of the macrophage are enhanced. LXR have been shown to repress the expression of several pro-inflammatory genes in the macrophage. These include the chemokines, monocyte chemoattractant protein-1 (MCP-1) and MCP-2, several genes whose products are involved in the production of bioactive molecules such as iNOS and COX2, and the inflammatory cytokines IL-1β and IL-6. Both LXRα and LXRβ are known to repress these inflammatory genes. Although there are numerous in vivo models of inflammation that are known to be repressed by LXR activation the precise mechanism exerted by the LXR is unclear since none of the repressed genes has had an LXRE identified in the proximal promoter region.
Role of LXR in Liver Lipid Homeostasis
In addition to their important role in cholesterol homeostasis, the LXR are critical regulators of overall hepatic lipogenesis. As in the role of LXR in cholesterol homeostasis, exerted via the activation of the expression of SREBP-1c, the lipogenic action of the LXR is also due to the activation of this master regulatory transcription factor.
Activation of LXR results in increased expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) both of which are required for de novo fatty acid synthesis. An additional enzyme involved in de novo fatty acid remodeling, whose expression is induced by LXR, is stearoyl-CoA desaturase (SCD). SCD is the rate-limiting enzyme catalyzing the synthesis of monounsaturated fatty acids, primarily oleate (18:1) and palmitoleate (16:1). These two monounsaturated fatty acids represent the majority of monounsaturated fatty acids present in membrane phospholipids, triglycerides, and cholesterol esters.
That LXR expression is critical to the regulation of these three enzymes of fatty acid synthesis is apparent from studies in the LXRα–/– mice where the reduction in SREBP-1c expression correlates to reduced expression of ACC1, FAS, and SCD. LXRs also induce the expression of genes involved in the remodeling of lipoprotein particles such as lipoprotein lipase, cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP).
The LXR have also been shown to be important in the regulation of hepatic glucose metabolism. Activation of LXR results in reduced expression of the hepatic gluconeogenesis genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase. In contrast, the hepatic glucokinase gene is induced by LXR. The net effect of these changes in hepatic glucose metabolism gene expression will be increased glucose utilization and reduced glucose output by the liver.
The LXRβ gene has been shown to enhance glucose-dependent insulin secretion by the pancreas and in LXRβ–/– mice this process is impaired. The effects of LXR activation on adipose tissue glucose utilization has also been demonstrated by the presence of an LXRE in the insulin-dependent GLUT4 gene promoter.
LXR Proteins as Therapeutic Targets
Given that LXR are important in the regulation of reverse cholesterol transport, exert an anti-inflammatory influence, and improve glucose tolerance suggests that they would be ideal targets for therapeutic purposes. However, the first generation synthetic LXR ligands activate both LXR and lead to marked increases in hepatic lipogenesis and plasma triglyceride levels. These effects are due to the role of LXR in activation of hepatic SREBP-1c and the resultant activation of each of its target genes as described above.
Although it could be theoretically possible to enhance the reverse cholesterol effects of LXR without targeting hepatic lipogenesis with the use of LXRβ-specific ligands since most of the hepatic responses are due to activation of LXRα, this will be a difficult challenge as the ligand binding pocket in both isoforms has been shown to be nearly identical. In addition, there are species-specific differences in overall LXR responses that need to be carefully considered meaning the use of animal models that more closely resemble humans in their metabolic pathways.