PMID- 21515403
OWN - NLM
STAT- MEDLINE
DCOM- 20120410
LR  - 20220409
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1821
IP  - 1
DP  - 2012 Jan
TI  - Modulation of RXR function through ligand design.
PG  - 57-69
LID - 10.1016/j.bbalip.2011.04.003 [doi]
AB  - 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 PPARgamma/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 PPARgamma/RXR and LXR/RXR heterodimer-selective rexinoids, which act 
      differently than PPARgamma or LXR agonists, might overcome some of these limitations.
CI  - (c) 2011 Elsevier B.V. All rights reserved.
FAU - Perez, Efren
AU  - Perez E
AD  - Departamento de Quimica Organica, Facultade de Quimica, Universidade de Vigo, 
      Spain.
FAU - Bourguet, William
AU  - Bourguet W
FAU - Gronemeyer, Hinrich
AU  - Gronemeyer H
FAU - de Lera, Angel R
AU  - de Lera AR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20110416
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Ligands)
RN  - 0 (Liver X Receptors)
RN  - 0 (Orphan Nuclear Receptors)
RN  - 0 (PPAR gamma)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus/metabolism
MH  - Humans
MH  - Insulin Resistance
MH  - Ligands
MH  - Liver X Receptors
MH  - Models, Molecular
MH  - Obesity/genetics/metabolism
MH  - Orphan Nuclear Receptors/chemistry/*metabolism
MH  - PPAR gamma/chemistry/*metabolism
MH  - Protein Multimerization
MH  - Protein Structure, Tertiary
MH  - Retinoid X Receptors/agonists/antagonists & inhibitors/*chemistry/*metabolism
MH  - Signal Transduction
MH  - Transcription Factors/chemistry/metabolism
MH  - Transcription, Genetic
EDAT- 2011/04/26 06:00
MHDA- 2012/04/11 06:00
CRDT- 2011/04/26 06:00
PHST- 2011/02/16 00:00 [received]
PHST- 2011/04/06 00:00 [revised]
PHST- 2011/04/07 00:00 [accepted]
PHST- 2011/04/26 06:00 [entrez]
PHST- 2011/04/26 06:00 [pubmed]
PHST- 2012/04/11 06:00 [medline]
AID - S1388-1981(11)00046-1 [pii]
AID - 10.1016/j.bbalip.2011.04.003 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2012 Jan;1821(1):57-69. doi: 10.1016/j.bbalip.2011.04.003. 
      Epub 2011 Apr 16.