Liver X receptor biology and pharmacology: new pathways, challenges and opportunities

doi:10.1016/j.tips.2012.03.013

Trends in Pharmacological Sciences

Volume 33, Issue 7, July 2012, Pages 394-404

https://doi.org/10.1016/j.tips.2012.03.013 Get rights and content

Nuclear receptors (NRs) are master regulators of transcriptional programs that integrate the homeostatic control of almost all biological processes. Their direct mode of ligand regulation and genome interaction is at the core of modern pharmacology. The two liver X receptors LXRα and LXRβ are among the emerging newer drug targets within the NR family. LXRs are best known as nuclear oxysterol receptors and physiological regulators of lipid and cholesterol metabolism that also act in an anti-inflammatory way. Because LXRs control diverse pathways in development, reproduction, metabolism, immunity and inflammation, they have potential as therapeutic targets for diseases as diverse as lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Recent insights into LXR signaling suggest future targeting strategies aiming at increasing LXR subtype and pathway selectivity. This review discusses the current status of our understanding of LXR biology and pharmacology, with an emphasis on the molecular aspects of LXR signaling that constitute the potential of LXRs as drug targets.

Section snippets

The oxysterol receptors LXRα and LXRβ are members of the NR family of transcription factors

The 48 members of the NR family in humans are master regulators of transcriptional programs that integrate the homeostatic control of almost all biological processes including development, reproduction, cell growth, metabolism, immunity and inflammation. Most NRs appear to regulate gene expression in response to small lipophilic compounds such as steroids, thyroid hormone, fatty acids and cholesterol metabolites. As ligands, these compounds directly bind to the NR ligand-binding domain (LBD)

LXRs as regulators of metabolic function

LXRβ is ubiquitously expressed at a moderate level in most physiological systems, whereas LXRα expression is mostly restricted to metabolically active tissues (www.nursa.org). It is important to note that this is merely based on quantification of mRNA levels and that protein expression levels (and protein stability) are largely unknown. The first studies on the physiological roles of LXR revealed key functions in the control of cholesterol metabolism [14] and lipogenesis [15] in the liver, a

LXRs regulate inflammatory responses and immunity

Considerable evidence has identified both LXRα and LXRβ as anti-inflammatory transcription factors and physiological regulators of innate and adaptive immune responses, apoptosis and phagocytosis. The first studies linking LXRs to inflammatory responses revealed that LXRs antagonized cytokine-mediated expression of proinflammatory genes in macrophages; it was suggested that this is a consequence of transcriptional silencing of the proinflammatory transcription factor nuclear factor (NF)-κB [6].

LXR pathways in cancer cells

LXRs appear to have dual roles in cancer biology. First, LXRs suppress the proliferation of a variety of human cancer cells [86], and second, tumors produce LXR agonists (oxysterols) that inhibit a robust immune response as a mechanism of tumor escape from immune surveillance [55]. At the molecular level, LXRs target the cell cycle at several points. LXRs reduce the expression of positive cell-cycle regulators, whereas they increase the expression of cell-cycle inhibitors. Although LXRs control

Molecular mechanisms of LXR action: focus on cistromes, PTMs and transrepression

According to conventional models, it is assumed that unliganded LXRs are constitutively nuclear and interact with corepressors such as NCoR/SMRT (nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid receptor) on DNA [92]. On binding of ligand to LXRs, the corepressor complex dissociates and coactivators are recruited, leading to activation of transcription (Figure 3a). Recent experiments using chromatin-immunoprecipitation (ChIP)-based techniques, including

Perspectives

The LXR involvement demonstrated in various metabolic, inflammatory and proliferative disease pathways makes them highly interesting pharmaceutical targets for novel therapies (Figure 4). However, current synthetic agonists cause activation of hepatic lipogenic enzymes via LXRα, thereby increasing triglyceride levels, a known risk factor for cardiovascular disease [105]. Clinical trials in humans using the LXR-623 agonist, which appears to activate LXR without causing hepatic lipogenesis, were

Concluding remarks

The recent discoveries of LXR-regulated pathways in inflammation and proliferation, in addition to the well-established role of LXRs in metabolism, have ignited new promise for LXRs as drug targets for metabolic disorders, chronic inflammatory diseases, cancer and neurodegenerative diseases. However, the broad physiological roles of LXRs involve a high risk of unwanted side effects, the most significant being an increased lipogenic profile. This suggests that successful drug development must

Acknowledgments

This study was supported by grants from the Center for Biosciences (E.T., J-Å.G), the Novo Nordisk Foundation (E.T.), the Swedish Research Council (E.T., J-Å.G., K.R.S.), the Welch Foundation (J-Å.G.) and the Emerging Technology Fund of Texas (J-Å.G.). K.R.S. holds a research assistant professorship from the Swedish Research Council (contract no. 522-2008-3745).

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Trends in Pharmacological Sciences

ReviewLiver X receptor biology and pharmacology: new pathways, challenges and opportunities

Section snippets

The oxysterol receptors LXRα and LXRβ are members of the NR family of transcription factors

LXRs as regulators of metabolic function

LXRs regulate inflammatory responses and immunity

LXR pathways in cancer cells

Molecular mechanisms of LXR action: focus on cistromes, PTMs and transrepression

Perspectives

Concluding remarks

Acknowledgments

Trends Endocrinol. Metab.

Mol. Cell

J. Biol. Chem.

Mol. Cell. Endocrinol.

J Biol Chem

Cell

J. Biol. Chem.

Cell Metab.

Cell

J. Lipid Res.

Neuroscience

Mol. Cell

J. Neuroimmunol.

Biochem. Biophys. Res. Commun.

J. Hepatol.

Gastroenterology

J. Biol. Chem.

Blood

Am. J. Pathol.

J. Biol. Chem.

J. Biol. Chem.

Osteoarthr. Cartil.

Biochim. Biophys. Acta

Adv. Immunol.

Cell Stem Cell

Med. Hypothese

Cell

Mol. Cell

Mol. Cell

Mol. Cell

FEBS Lett.

Evolution of NURSA, the nuclear receptor signaling atlas

Mol. Endocrinol.

Principles for modulation of the nuclear receptor superfamily

Nat. Rev. Drug Discov.

The different roles of ER subtypes in cancer biology and therapy

Nat. Rev. Cancer

The nuclear receptor superfamily and drug discovery

ChemMedChem

Liver X receptors as integrators of metabolic and inflammatory signaling

J. Clin. Invest.

A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily

Mol. Cell. Biol.

OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor

Proc. Natl. Acad. Sci. U.S.A.

Crystal structure of the heterodimeric complex of LXRα and RXRβ ligand-binding domains in a fully agonistic conformation

EMBO J.

Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ

Genes Dev.

Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice

J. Clin. Invest.

Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

J. Clin. Invest.

Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo

J. Clin. Invest.

Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo

Circulation

Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels

Circ. Res.

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

J. Clin. Invest.

LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor

Science

Separate and overlapping metabolic functions of LXRα and LXRβ in C57Bl/6 female mice

Am. J. Physiol. Endocrinol. Metab.

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity

Proc. Natl. Acad. Sci. U.S.A.

Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals

J. Mol. Endocrinol.

Review
Liver X receptor biology and pharmacology: new pathways, challenges and opportunities