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The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signaling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and myocardial ischemia/reperfusion injury and diabetic cardiomyopathy.
LXR, two members of the nuclear receptor superfamily
Liver X receptor (LXR) α (NR1H3) and LXRβ (NR1H2) belong to a subclass of the nuclear receptor superfamily, which form obligatory heterodimers with retinoid X receptor (RXR), the receptor of 9-cis retinoic acid. In humans LXRα and LXRβ are encoded by two distinct genes located on chromosomes 11p11.2 and 19q13.3, respectively. LXR were initially isolated from a human liver cDNA library as orphan receptors. Later, oxysterols, which are oxidized derivatives of cholesterol, were identified as their natural ligands and the first physiological functions were associated with cholesterol homeostasis.
Most endogenous sterols that activate LXRs can also inhibit the activation of the SREBP pathway, which underscores that the LXR and SREBP pathways are highly interconnected in control of cholesterol homeostasis. In contrast to endogenous sterols, most synthetic LXR agonists do not inhibit SREBP processing, which demonstrates that the two pathways can be pharmacologically separated and potentially targeted independently.
The two LXR isotypes share substantial sequence identity and possess a domain structure that is common to most nuclear receptors. Of particular relevance to drug discovery, the ligand-binding domains of the two LXRs have very similar primary sequences; this has made it difficult to identify small molecules that bind to one LXR and not the other. The transcriptional activity of LXRs is dependent on the formation of heterodimers with retinoid X receptors4 (RXRs) (Figure. 1). In the absence of a bound ligand, the LXR–RXR heterodimer is believed to remain bound to the promoter region of its target genes (as discussed below) in complex with co‑repressors, thus inhibiting target gene activation. Indeed, deletion of LXRs in some cell types has been associated with the elevated mRNA expression (de‑repression) of certain target genes such as ATP-binding cassette subfamily A member 1(ABCA1).
Figure 1. LXR–RXR heterodimers are ligand-activated transcription factors.
LXRs and reverse cholesterol transport
Cholesterol removal from non-hepatic cells and its delivery back to the liver for excretion are processes collectively known as reverse cholesterol transport (RCT) (Figure 2). Elevated flux through the RCT pathway is thought to protect against cardiovascular diseases primarily by facilitating the removal of cholesterol from macrophage foam cells in atherosclerotic plaques. Several direct LXR target genes are closely associated with the RCT pathway, including genes encoding membrane lipid transporters, such as ATP-binding cassette subfamily A type 1 (ABCA1), ABCG1, ABCG5 and ABCG8; apolipoproteins (Apos), such as ApoE; and lipid transfer proteins and cholesterol metabolizing enzymes, such as cholesterol 7-α-hydroxylase (CYP7A1).
At the cellular level, ABCA1 and ABCG1 transport cellular cholesterol to ApoA1 and high-density lipoprotein (HDL), respectively. Then, the lipidated lipoprotein particles transport cholesterol back to the liver via low-density lipoprotein receptor (LDLR) and HDL receptor scavenger receptor class B type 1 (SR-B1), which perform selective lipid uptake from HDL into hepatocytes. Finally, the cholesterol is secreted into bile or catabolized into bile acids via a process that is modulated by CYP7A1. In Lxr-/- mice, cholesterol removal from the body is severely impaired. In contrast, the systemic activation of LXRs in mice by synthetic LXR agonists reduces plasma cholesterol levels and raises plasma HDL levels.
Figure 2. LXRs regulate reverse cholesterol transport.
LXRs in atherosclerosis
Cardiovascular disease has been the primary disease indication driving the development of LXR agonists thus far. In both Apoe-null and Ldlr-null mice, the synthetic pan-LXR agonist GW3965 inhibited the development of aortic lesions. These findings were subsequently confirmed using several other mouse models and LXR agonists. The beneficial effects of LXR agonism on lesion development were observed even in the absence of changes in plasma cholesterol levels, which suggests that LXR was acting primarily to prevent cholesterol deposition in macrophages and to promote flux through the reverse cholesterol transport pathway. Indeed, macrophages lacking LXRs accumulate cholesteryl ester and rapidly become foam cells in vitro. Furthermore, the expression of key genes involved in cholesterol efflux is induced in lesions following the administration of an LXR agonist to mice, and deletion of both LXRα and LXRβ on the Apoe-null background leads to extensive foam cell formation, atherosclerosis and death by 10 weeks of age.
A central role for macrophage signaling in the development of atherosclerosis was further established by studies in which bone marrow from LXR-deficient animals was transplanted into LDLR-deficient mice. The absence of LXRα and LXRβ expression was associated with markedly increased development of lesions in the recipient mice. The importance of the LXR pathway in macrophages in vivo is also supported by studies showing that transgenic LDLR-null mice overexpressing LXRα from a macrophage-specific promoter had reduced atherosclerosis in the absence of a change in plasma lipid levels. Finally, the anti-atherogenic effects of an LXR agonist are blunted in LDLR-null mice that are transplanted with bone marrow lacking both LXRα and LXRβ or lacking ABCA1. These promising preclinical data have stimulated widespread interest in the development of LXR agonists as drugs for cardiovascular disease. Various LXR agonists have advanced to clinical trials and the resulting data have improved the understanding of the potential benefits and limitations of targeting LXRs in humans.
In summary, increasing evidence produced by basic research suggests that the activation of LXRs protects the heart from several cardiovascular diseases. Numerous regulators and signaling targets of LXRs have provided researchers with many opportunities to explore their underlying mechanisms. With the in-depth understanding of LXR biology and the development of innovative drug discovery strategies, several LXR isotype-selective agonists have emerged and even entered clinical trials. Unfortunately, no compounds have yet been approved by the US FDA for clinical treatment due to several unexpected side effects, such as adverse CNS events. However, it is undeniable that LXRs are important therapeutic targets for cardiovascular diseases and maintaining cholesterol homeostasis. Thus, the advancement of drug discovery programs could promote the development of safe and effective LXR agonists for future clinical applications.