PPARbeta: a member of the nuclear receptor superfamily

Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the class of nuclear receptors that modulate target gene expression in response to endogenous and exogenous ligands (Michalik et al., 2006). PPARbeta (= PPARdelta), like the PPARalpha and PPARgamma subtypes, shows basal transcriptional activity in the absence of ligand binding (Molnar et al., 2005). It is activated by arachidonic acid (and to a lesser extent by some other fatty acids and fatty acid derivatives; Forman et al., 1997), and is therefore thought to act as a intracellular lipid sensor (Michalik et al., 2006). PPARbeta is a highly relevant drug target, which lead to the development of several synthetic drug agonists displaying subtype selectivity and high-affinity binding, such as GW501516 and L165041 (Peraza et al., 2006). After ligand binding, PPARbeta forms obligatory heterodimers with the nuclear receptor RXR on PPAR response elements (PPREs) in target genes resulting in their transcriptional activation. PPARbeta probably can also repress genes by directly interacting with specific transcription factors (Lee et al. 2003) or sequestration of RxR from other RxR-dependent nucelar receptors (Matsusue et al., 2006).

The mouse Pparb gene

The mouse Pparb (Ppard, Nuc1) gene is located on chromosome 17. Its transcribed region spans 88,666 bp from positions 27,960,392 to 28,029,058 (Ensembl). Pparb is split into 8 exons giving rise to a mRNA of 3,169 bases encoding the full-length 440 amino acid murine PPARbeta.

The human PPARB gene

The human PPARB (PPARD, NUC1) gene is located on chromosome 6. Its transcribed region spans 85,564 bp from positions 35,418,369-35,503,933 (Ensembl). Pparb is split into 9 exons giving rise to a mRNA of 3,774 bases encoding the full-length 441 amino acid human PPARbeta.

PPARbeta in metabolism and inflammation

Major functions of the PPARbeta protein are associated with the regulation of intermediary metabolism, in particular energy homeostasis, lipid catabolism and glucose metabolism (Desvergne et al., 2006). PPARbeta also figures in the control of inflammatory responses by two major mechanisms: (i) modulation of the functional state of immune cells by regulating the expression of cytokines, adhesion molecules and extracellular matrix proteins, and (ii) regulation of the proliferation, differentiation and survival of macrophages and lymphocytes (Kostadinova et al., 2005). PPARbeta therefore represents a highly relevant drug target for the treatment of major human diseases such as obesity, metabolic syndrome, inflammatory diseases and arteriosclerosis.

PPARbeta in development

Mice lacking PPARbeta show a very high degree of embryonic lethality due to an aberrant development and malfunction of the placenta (Peters et al., 2000; Barak et al., 2002; Nadra et al., 2006). Consistent with this finding, the differentiation and metabolic functions of trophoblast giant cells in vitro are dependent on PPARbeta (Nadra et al., 2006). Pparb null mice also exhibit a defect in wound healing (Michalik et al., 2001), and consistent with this observation, PPARbeta is critical for the survival of keratinocytes by upregulating the PI3K-AKT survival pathway (DiPoi et al., 2002). PPARbeta also stimulates keratinocyte differentiation and inhibits proliferation (Peters et al., 2000; Burdick et al., 2006), concomitant with a down-regulation of protein kinase C and MAP kinase signaling (Kim et al., 2005). Another tissue where PPARbeta play a role in differentiation is the digestive tract, where PPARbeta promotes the differentiation of Paneth cells in the intestinal crypts by down-regulating the hedgehog signaling pathway (Varnat et al., 2006).

PPARbeta in tumorigenesis

Consistent with its function in differentiation and proliferation PPARbeta plays a role in intestinal tumorigenesis. In the Apc/Min mouse mice lacking functional APC protein as well as in azoxymethane-induced intestinal carcinogenesis PPARbeta has been described to affect tumor growth in different studies. However, the homozygous deletion of Pparb (Barak et al., 2002; Harman et al., 2004; Reed et al., 2004) as well as the pharmacological activation of PPARb (Gupta et al., 2004; Marin et al., 2006) exerted subtle though partly contradictory effects on adenoma growth. The reason for these discrapencies, and thus the precise function of PPARbeta in intestinal tumor cells, remain unclear at present. Apart from its role in intestinal oncogenesis, PPARbeta has been reported to figure in TPA-triggered skin carcinogenesis (Peters et al., 2000). Finally, our own work suggests that PPARbeta also has an essential function in the tumor stroma (Müller-Brüsselbach et al., 2007). Thus, we observed a severe defect in tumor vascularization in Pparb null mice, which apparently arises from the hyperproliferation of ECs and a lack of microvessel maturation specifically in the tumor microenvironment.

Useful Links

PubMed - OMIM

The PPAR Resource (Penn State University)

Nuclear Receptor (Journal Homepage)

Nuclear Receptor Signaling Atlas (NURSA)