Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases

B. L. Balint, L. Nagy

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well as cofactor binding. A key aspect of this is that unlike classical steroid hormone receptors such as the retinoic acid receptor, the PPAR receptors have a rather large ligand-binding pocket which is not filled with the ligand entirely and the ligand also stabilizes the receptor's structure. The liganded receptor can have distinct conformations and this leads to different binding affinities for the various cofactors (coactivators and corepressors). In this review, we will introduce this concept, review the literature that supports it and present an overview of the receptor selective ligands including data about their mechanism of action and biological effects.

Original languageEnglish
Pages (from-to)33-43
Number of pages11
JournalEndocrine, Metabolic and Immune Disorders - Drug Targets
Volume6
Issue number1
Publication statusPublished - Mar 2006

Fingerprint

Peroxisome Proliferator-Activated Receptors
Metabolic Diseases
Ligands
Therapeutics
Selective Estrogen Receptor Modulators
Co-Repressor Proteins
Retinoic Acid Receptors
Steroid Receptors
Metabolic Networks and Pathways
Lipid Metabolism
Insulin Resistance
Atherosclerosis
Obesity
Hormones
Gene Expression
Pharmaceutical Preparations

Keywords

  • Diabetes
  • Dyslipidemia
  • Ligands
  • PPARs
  • SPPARMs

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy

Cite this

Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases. / Balint, B. L.; Nagy, L.

In: Endocrine, Metabolic and Immune Disorders - Drug Targets, Vol. 6, No. 1, 03.2006, p. 33-43.

Research output: Contribution to journalArticle

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