The liver X receptors (LXRs) are sterol-sensitive transcription factors that regulate cholesterol homeostasis.
LXRs control the expression of genes that are linked to lipid synthesis, transport and excretion in many tissues.
LXRs are crucial regulators of the reverse cholesterol transport pathway and are important determinants of whole-body cholesterol content.
Pharmacological activation of LXRs inhibits the development of atherosclerosis in animal models.
Subtype-selective LXR agonists and tissue-selective agonists are promising strategies for the development of targeted modulators of lipid metabolism.
Alterations in LXR-dependent gene expression and cholesterol metabolism have been associated with the development of neurological diseases, including Alzheimer's disease.
LXR is a promising therapeutic target but the development of novel drugs faces many challenges, including undesirable hepatic side effects.
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 signalling 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 Alzheimer's disease.
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P.T. is an investigator of the Howard Hughes Medical Institute and his research was supported by the US National Institutes of Health (NIH) grant HL-066088. The research of C.H. is supported by a grant from the American Heart Association (13BGIA17110079).
The authors declare no competing financial interests.
AtheroNova website — 5 December 2013 press release (“AtheroNova Completes Enrollment in Phase 1 Clinical Trial of AHRO-001, a Potential Treatment for Atherosclerosis”)
- Low-density lipoprotein receptor
(LDLR). The primary receptor for LDL clearance from the circulation; it is found on the plasma membrane, with highest levels of expression in the liver. Genetic mutations in this protein are linked to familial hypercholesterolaemia.
Derivatives of cholesterol, some of which act as endogenous ligands for the liver X receptor.
- Retinoid X receptors
(RXRs). Members of the nuclear receptor superfamily that exist as three subtypes — RXRα, RXRβ, RXRγ — and bind to the endogenous ligand 9-cis retinoic acid.
- ATP-binding cassette subfamily A member 1
(ABCA1). A membrane-bound transporter with high levels of expression in the liver and macrophages. ABCA1 transports cholesterol and phospholipids to apolipoproteins. Mutations in the protein cause Tangier disease.
- DR4 response element
A DNA-binding motif that consists of four base pairs separating a repeating 6-mer. The canonical direct repeat 4 (DR4) motif bound by liver X receptors is AGGTCAnnnnAGGTCA (where 'n' refers to any nucleotide).
- Apolipoprotein E
(APOE). A protein that is primarily synthesized in the liver and functions to transport lipoproteins. Mutations in APOE have been associated with lipid disorders and Alzheimer's disease.
- Reverse cholesterol transport
A pathway in which cholesterol is returned from the periphery back to the liver for redistribution or excretion.
- Phospholipid transfer protein
(PLTP). A protein that transfers phospholipids from triglyceride-rich lipoproteins to high-density lipoproteins, and is highly expressed in the liver.
- Cholesteryl ester transfer protein
(CETP). A protein that transfers cholesterol esters from high-density lipoprotein (HDL) to triglyceride-rich lipoproteins in humans.
- ob/ob mouse
A genetically modified mouse that is leptin-deficient and widely used as a model of obesity and insulin resistance.
- Foam cells
Lipid-laden macrophages that are found in atherosclerotic lesions.
- FERM domain
A protein–protein interaction domain (containing 4.1 protein, ezrin, radixin and moesin) that is found in membrane-associated proteins.
- RING domain
A zinc finger motif that is characteristic of E3 ubiquitin ligases.
- Smith–Lemli–Opitz syndrome
A syndrome that is characterized by 7-dehydrocholesterol reductase deficiency. It is autosomal recessive and phenotypically characterized by distinct facial features, small head size and intellectual disabilities.
- Niemann–Pick type C disease
A disease that is caused by a genetic mutation in either Niemann–Pick C1 protein (NPC1) or NPC2, resulting in the cellular accumulation of unesterified cholesterol.
- Amyloid-β peptides
The primary element of the amyloid plaques that are found in patients with Alzheimer's disease.
- APP-transgenic mice
Genetically modified mice that overexpress a form of amyloid precursor protein (APP) with mutations that are associated with familial Alzheimer's disease.
- Full agonists
Ligands that bind to and activate a receptor to achieve a maximal response for that receptor.
- Inverse agonists
Ligands that bind to a receptor and induce a response that is opposite to that induced by an agonist of that receptor: that is, they reduce the basal activity of the receptor.
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Hong, C., Tontonoz, P. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov 13, 433–444 (2014). https://doi.org/10.1038/nrd4280
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