Abstract
The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation—where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα—is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression—where PPARγ alters gene expression independent of DNA binding—is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ’s target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.
Highlights
PPARg2, containing an additional 28 amino acids in its NH2-terminus, is almost exclusively expressed in adipose tissue. This isoform is expressed in urothelial cells [4, 5], which are highly specialized transitional epithelial cells that line the organs of the urinary system, including the bladder, and in regulatory T cells (Tregs) and other T cell populations, albeit that total PPARg expression is low in non-Tregs [6]
The ligand binding domain (LBD) is a key domain for transactivation of PPARg target genes as it is implicated in ligand binding, heterodimerization with binding partner retinoid X receptor alpha (RXRa), and interactions with transcriptional co-regulators
The importance of PPARg for white adipose tissue biology in humans is underscored in patients suffering from familial partial lipodystrophy subtype 3 (FPLD3), a rare autosomal dominant inherited condition caused by loss-of-function mutations in the PPARG gene [reviewed in [28]]
Summary
Since its discovery in the early 1990s by Tontonoz et al [1]., the nuclear receptor PPARg, encoded by the PPARG gene on chromosome 3p25.2 in humans (Figure 1A) [2], has been recognized as the master regulator of adipose tissue biology. The LBD is a key domain for transactivation of PPARg target genes as it is implicated in ligand binding, heterodimerization with binding partner retinoid X receptor alpha (RXRa), and interactions with transcriptional co-regulators. To the “classical” transactivation mechanism described above, PPARg can negatively regulate gene expression by a mechanism referred to as ligand-dependent transrepression (Figure 3B) This mechanism involves antagonizing the NF-kB and AP-1 pro-inflammatory signaling pathways, and has been mostly described in immune cells [19,20,21,22,23]. MRL24 that displays poor agonistic activity but robust anti-diabetic activity in mice [47], was very effective in inhibiting the Cdk5-mediated phosphorylation [30] This suggests that new classes of antidiabetic drugs that i) bind with high affinity to PPARg, ii) target the Cdk5-mediated phosphorylation of S273, and iii) completely lack the classical transcriptional agonism, hold promise for treatment of T2DM. Allosteric modulators that target the alternate site might be relevant for obese individuals in which the probability that canonical LBP is occupied by oxidized fatty acids due to increased bioavailability of endogenous ligands is increased [49]
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