Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewMolecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes
Introduction
Peroxisome Proliferator-Activated Receptor (PPAR) α (NR1C1), β/δ (NR1C2) and γ (NR1C3) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily [1]. PPARs are lipid sensors capable of adapting gene expression to integrate various lipid signals coming from intracellular signaling pathways, from inter-organ crosstalk or even from the diet [2]. Given their partially overlapping yet specific expression patterns, the three receptors cooperate to efficiently regulate metabolic functions [3], [4] as well as other cellular processes such as proliferation, differentiation or apoptosis that are essential to the fate of the tissues and organs in which they are expressed [2], [5].
PPARs have a canonical nuclear receptor organization. The N-terminal A/B domain does not seem to be structured and harbors a weak ligand-independent transactivation function called AF-1. The C domain binds DNA via a two zinc-finger motif that is the hallmark of the nuclear receptor superfamily. Following the D domain which is a hinge region, the E domain harbors the ligand binding domain (LBD) and is endowed with a ligand-dependent transactivation function referred to as AF-2. This domains allows PPARs to function as lipid or xenobiotic sensors, since, as we will see later on, the binding pocket is large and can accommodate numerous structures. In addition, the E domain also offers the main surfaces for dimerization as well as for interaction with regulatory proteins called coregulators, a key aspect of PPAR modulation that we will also further develop in this review.
PPARs are very important pharmaceutical targets, as specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders [6]. More precisely, fibrates are PPARα agonists used as plasma lipid-lowering drugs in the treatment of hyperlipidaemia. Compounds of the class of the thiazolinediones (TZDs), such as Troglitazone, Pioglitazone and Rosiglitazone are PPARγ agonists and potent insulin-sensitizers, which have been tested and compared in a number of clinical trials for the treatment of type 2 diabetes (reviewed in [7]).
The PPARγ gene can be transcribed into three mRNA species, i.e. PPARγ1, PPARγ2, and PPARγ3 [8], [9]. Little is known about the expression pattern of PPARγ3, except that it appears to be the predominant PPARγ type in macrophages. PPARγ1 seems ubiquitously expressed, whereas PPARγ2 expression is confined to the adipose tissue, underscoring the importance of the PPARγ form for adipocyte physiology. Both the γ1 and γ2 isoforms display adipogenic potential although PPARγ2 seems slightly more potent owing to higher affinity with certain coactivators [10]. The specific genetic invalidation of PPARγ2 in the adipose tissue revealed that both isoforms are important for adipocyte physiology [11], [12]. However, it is so far not clear which specific role each isoform plays in glucose and lipid homeostasis. The specificity of action may in part rely on their different tissue expression patterns, but also in the modulation of receptor activity by the presence in PPARγ2 of an additional domain of 30 residues at the N-terminus.
Section snippets
The causes of type 2 diabetes
Type 2 diabetes is clinically defined by a hyperglycemia in fasted patients, resulting primarily from a desensitization to the hypoglycaemic actions of insulin. The etiology of type 2 diabetes is however a complex issue, since it is a heterogeneous disease with multiple and intricate causes [13], which may be of relative importance depending upon the genetic background and life-style of the subjects affected [14]. Nevertheless, obesity and dyslipidaemia constitute two overwhelming factors in
PPARγ partial activation versus modulation
These observed or potential side-effects are of great concern and raise the question of whether the modulation of PPAR activation may become safer while retaining its efficacy. Pharmaceutical developments have until recently focused on more potent and specific activators of PPARγ, the rational being to decrease the doses used during the treatment, thereby reducing the non-specific interactions of these drugs with other cellular components. However, this strategy was greatly challenged when
PPARs can bind a wide variety of ligands owing to their large ligand binding pocket
SPPARγMs are ligands whose binding induces a specific conformation change of the receptor, translating into the induction of a specific subset of target genes. A particularity of the PPAR sub-family is that the diversity of functions in which they are implicated is also reflected by the diversity of ligands that can be accommodated within their ligand binding pocket. Indeed, PPARs are activated by a wide range of naturally occurring or metabolized lipids derived from the diet or from
What is the profile of a good SPPARγM?
The SPPARγM described so far in the literature have been often only partly characterized, regarding ligand binding mode, conformational changes, coregulator recruitment, target gene activation and physiological response. To allow a better overview and the comparison of the different SPPARγMs, we summarized in a table the most important properties of each of these molecules (Table 1). It is hence very difficult to link with certitude a specific conformation change or the recruitment of a
Acknowledgements
This work was supported by grants from the National Research Project 50, the Swiss National Science Foundation, and the Etat de Vaud.
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The authors contributed equally to this work.
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