Modulation of RXR function through ligand design

doi:10.1016/j.bbalip.2011.04.003

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1821, Issue 1, January 2012, Pages 57-69

https://doi.org/10.1016/j.bbalip.2011.04.003 Get rights and content

Abstract

As the promiscuous partner of heterodimeric associations, retinoid X receptors (RXRs) play a key role within the Nuclear Receptor (NR) superfamily. Some of the heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) are “permissive” as they become transcriptionally active in the sole presence of either an RXR-selective ligand (“rexinoid”) or a NR partner ligand. In contrast, “non-permissive” heterodimers (including RAR/RXR, VDR/RXR and TR/RXR) are unresponsive to rexinoids alone but these agonists superactivate transcription by synergizing with partner agonists. Despite their promiscuity in heterodimer formation and activation of multiple pathways, RXR is a target for drug discovery. Indeed, a rexinoid is used in the clinic for the treatment of cutaneous T-cell lymphoma. In addition to cancer RXR modulators hold therapeutical potential for the treatment of metabolic diseases. The modulation potential of the rexinoid (as agonist or antagonist ligand) is dictated by the precise conformation of the ligand–receptor complexes and the nature and extent of their interaction with co-regulators, which determine the specific physiological responses through transcription modulation of cognate gene networks. Notwithstanding the advances in this field, it is not yet possible to predict the correlation between ligand structure and physiological response. We will focus on this review on the modulation of PPARγ/RXR and LXR/RXR heterodimer activities by rexinoids. The genetic and pharmacological data from animal models of insulin resistance, diabetes and obesity demonstrate that RXR agonists and antagonists have promise as anti-obesity agents. However, the treatment with rexinoids raises triglycerides levels, suppresses the thyroid hormone axis, and induces hepatomegaly, which has complicated the development of these compounds as therapeutic agents for the treatment of type 2 diabetes and insulin resistance. The discovery of PPARγ/RXR and LXR/RXR heterodimer-selective rexinoids, which act differently than PPARγ or LXR agonists, might overcome some of these limitations.

Research highlights

► RXRs are promiscuous partners in heterodimers with other nuclear receptors. ► Permissive heterodimers are responsive to ligands of each partner. ► Ligand structure is linked to cofactor interactions and physiological function. ► Rexinoids are promising drugs for the treatment of the Metabolic Syndrome. ► RXR/PPARγ and RXR/LXR heterodimer-specific rexinoids have been developed.

Introduction

In addition to being master regulators of gene networks that control cell growth, differentiation, survival and death, retinoid X receptors (RXRs) [1] play unique modulatory and integrative roles across multiple metabolic systems, forming obligate heterodimers with a large number of other NR superfamily members. An RXR selective ligand (“rexinoid”) bexarotene (LGD1069, Targretin®) [2] is used in therapy for the treatment of cutaneous T-cell lymphoma and is in clinical trials for the treatment of breast and lung cancer. An interesting novel cancer therapeutic perspective of rexinoids and PPARγ (peroxisome proliferator-activated receptor γ)-RXR selective agonists derives from the observation that these ligands induce, in conditions where growth factor action is inhibited, cancer cell apoptosis through induction of NO and activation of the intrinsic death pathway [3]. In addition to their applications in cancer [4], [5], rexinoids could be valuable in the treatment of diabetes and obesity (two major components of the Metabolic Syndrome), atherosclerosis, and other cardiovascular indications and inflammatory diseases [4], via signaling pathways that depend, among other factors, on the modulation of the heterodimers with the PPARs [6], and the liver X receptors (LXRs) [7], [8], [9], [10], [11].

RXRs are expressed in virtually every tissue of the body: RXRβ (NR2B2) is ubiquitously expressed; RXRα (NR2B1) is mainly expressed in liver, lung, muscle, kidney, epidermis, and intestine and is the major subtype in skin; and RXRγ (NR2B3) is found in brain, cardiac and skeletal muscle [1]. The data obtained with genetic models are consistent with the view that rexinoids play a fundamental role in the physiological regulation of energy balance acting via different pathways, such as appetite and fuel utilization. Mice in which RXRγ is deleted have increased metabolic rate, reduced food intake [12], and gained less weight than wild type animals when maintained on a high fat diet [12], [13], and showed increased activity of lipoprotein lipase in the skeletal muscle [14]. The RXRβ and RXRα subtypes may also be important in energy balance [15], and the latter in triglyceride storage and mobilization [16].

PPARα (NR1C1) stimulates lipid metabolism downregulating or upregulating genes involved in fatty acid uptake and degradation, and in reverse cholesterol transport. PPARγ (NR1C3) acts as regulator of adipocyte differentiation as well as other processes that affect metabolism. Together, the α and γ subtypes regulate the balance between catabolism and storage of long-chain fatty acids. Activation of PPARβ/δ (NR1C2) increases high-density lipoprotein (HDL) cholesterol levels, exerts glycemic control and improves glucose tolerance and insulin resistance in ob/ob mice, which are used as a model of noninsulin-dependent diabetes mellitus (NIDDM) [6].

LXR regulates cholesterol homeostasis and determines atherosclerosis susceptibility [17]. LXRα (NR1H2) drives cholesterol metabolism in the liver, whereas LXRβ (NR1H3) activates reverse cholesterol transport from the peripheral tissues to the liver by increasing the levels of plasma HDLs. Excretion of cholesterol is due to the increased expression levels of members of the ATP-binding cassette (ABC) family of membrane transporters [7]. Cholesterol balance also depends on the activity of CYP7A1, cholesterol 7α-hydroxylase, the rate-limiting enzyme of bile acid synthesis and a target of LXR/RXR heterodimers [18]. Alteration of the cholesterol homeostasis in macrophages can lead to the development of atherosclerotic lesions, in particular if the protective role of apolipoprotein E (ApoE) is impaired.

A cross-talk of LXR and PPAR is established in the homeostasis of fatty acids, since LXR regulates their synthesis and PPAR controls their degradation. In fact, the LXRα gene is a direct target of PPARγ, and stimulation of PPARγ by agonists has been shown to increase ABCA1 expression by raising LXRα levels [17]. Activation of LXR by synthetic LXR ligands increases overall hepatic lipogenesis and plasma triglyceride levels, due to the increased expression of enzymes and proteins involved in de novo fatty acid synthesis. LXRs are also involved in hepatic carbohydrate metabolism [19], and their activation results in increased glucose utilization and reduced glucose output by the liver due to the combined effect of the induction of hepatic glucokinase and reduced expression of some hepatic gluconeogenesis genes. LXR activation also regulates cellular fuel utilization in adipocytes [19], and stimulates human adipocyte lipolysis [20].

Section snippets

Activation of permissive PPAR/RXR and LXR/RXR heterodimers

Being permissive heterodimers PPARs/RXRs and LXR/RXRs are activated by both rexinoids as well as agonists of the partner receptors. In fact, RXR agonists can display pharmacological activities [4] that reflect activation of these partners, for example, insulin sensitization for PPARγ, which is the target of the anti-diabetic drugs [21], [22], and cholesterol, fatty acid and glucose homeostasis for LXR, which is activated by oxysterols [23], [24].

Both rexinoids and PPARγ agonists produce insulin

Structural basis of rexinoid action

The comparison of the crystal structures of the ligand binding domain (LBD) of unliganded (apo)-RXR [49] and agonist-bound (holo)-RXR [50] led to the proposal of the “mouse trap” mechanism of ligand-induced trans-conformation in RXR [51]. The LBD of NRs is a single protein domain organized in a primarily helical scaffold termed “anti-parallel alpha-helical sandwich.” Apo-RXR LBD contains 12 α-helices and a short (s1-s2) β-turn arranged in three layers, the C-terminal helix H12 protruding out of

Rexinoid roles in heterodimers

The so-called selective RXR modulators are an important class of rexinoid ligands, since they exhibit heterodimer selectivity. In addition, the rexinoid might act as agonist or antagonist of heterodimers with different partners in preference to others or to the RXR homodimers. As the functional consequences of rexinoid binding will be primarily determined by the ligand, different agonistic and antagonistic structures should result in different actions on coregulator interactions and RXR

RXR-subtype selective ligands

All residues belonging to H3, H5, H7 and H11, and the β-turn, which constitute the ligand-binding pocket of RXR, are highly conserved in all three subtypes (α,β and γ), thus complicating the discovery of subtype-selective rexinoids. Nevertheless, despite the identity of the aminoacids in direct contact to the ligand, the residues on the second layer might allow the receptor to display selectivity by differential flexibility. The repositioning of N306 observed in some crystal structures such as

Natural RXR ligands

The consideration of 9-cis-retinoic acid as a bona fide endogenous RXR ligand is controversial [70], and experiments have shown that it is unlikely the case under physiological conditions [71]. This opens up the possibility that other yet uncharacterized re(t)xinoids could be physiological RXR ligands. Recent reports have shown the presence in vivo of biologically potent vitamin A derivatives. Among others, dihydroretinoids produced by retinol saturase (RetSat), which control physiological

Conclusion

RXR is a combinatorial partner for ca. one third of the human nuclear receptor superfamily members. The recent research in rexinoid action has revealed several novel and exciting paradigms that are key for advancing drug discovery. The enormous gain in knowledge about the link between three-dimensional structures, ligand-induced allosteric changes and the resulting abilities of the RAR/RXR heterodimer to communicate with the intracellular microcosmos are major steps toward the design of

Acknowledgments

Work from our laboratories was partially supported by funds from theMICINN (SAF-2010-17395-FEDER, AdL), the Xunta de Galicia (INBIOMED; Project 08CSA052383PR from DXI + D+i, AdL), the Association for International Cancer Research (HG), the Ligue National Contre le Cancer (HG; laboratoire labelisé), the French National Research Agency (WB; ANR-07-PCVI-0001-01), and the European Community contracts QLK3-CT2002-02029 “Anticancer Retinoids” (AdL, HG), LSHM-CT-2005-018652 “Crescendo” (HG) and

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ReviewModulation of RXR function through ligand design

Abstract

Research highlights

Introduction

Section snippets

Activation of permissive PPAR/RXR and LXR/RXR heterodimers

Structural basis of rexinoid action

Rexinoid roles in heterodimers

RXR-subtype selective ligands

Natural RXR ligands

Conclusion

Acknowledgments

Cancer Cell

FEBS Lett.

J. Clin. Invest.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biol. Med.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Mol. Cell

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Cell

Bioorg. Med. Chem. Lett.

J. Lipid Res.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

J. Biol. Chem.

Metabolism

Bioorg. Med. Chem. Lett.

The pharmacology and classification of the nuclear receptor superfamily. RETINOID X RECEPTORS (RXRs)

Pharmacol. Rev.

Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells

J. Med. Chem.

RAR and RXR modulation in cancer and metabolic disease

Nat. Rev. Drug Discov.

Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer

Nat. Rev. Cancer

International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors

Pharmacol. Rev.

International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptor

Pharmacol. Rev.

Retinoid X receptor heterodimers in the metabolic syndrome

New Engl. J. Med.

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Proc. Natl. Acad. Sci. USA

Attenuation of colon inflammation through activators of the retinoid X receptor (RRX)/peroxisome proliferator-activated receptor γ (PPARγ) heterodimer

J. Experim. Med.

Retinoid X receptorγ-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet

Endocrinology

Temporal changes in gene expression in the arcuate nucleus precede seasonal responses in adiposity and reproduction

Endocrinology

RXR gamma null mice are apparently normal and compound RXRα+/−/RXRγ−/−/RXRγ−/− mutant mice are viable

Proc. Natl. Acad. Sci. USA

Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor α mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes

Proc. Natl. Acad. Sci. USA

Nuclear receptors and lipid physiology: opening the X-files

Science

Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers

Science

Role of LXRs in control of lipogenesis

Genes Dev.

The biology of peroxisome proliferator-activated receptors

Diabetes

LXR, a nuclear receptor that defines a distinct retinoid response pathway

Genes Dev.

Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists

Nature

The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction

Diabetologia

Activation of the Retinoid X Receptor suppresses appetite in the rat

Endocrinology

Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes

J. Clin. Inv.

Review
Modulation of RXR function through ligand design

RXR gamma null mice are apparently normal and compound RXRα^+/−/RXRγ^−/−/RXRγ^−/− mutant mice are viable

Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor α mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ER^T2) in adipocytes