Regulation of Matrix Remodeling by Peroxisome Proliferator-Activated Receptor-γ: A Novel Link Between Metabolism and Fibrogenesis

Abstract

The intractable process of fibrosis underlies the pathogenesis of systemic sclerosis (SSc) and other diseases, and in aggregate contributes to 45% of deaths worldwide. Because currently there is no effective anti-fibrotic therapy, a better understanding of the pathways and cellular differentiation programs underlying fibrosis are needed. Emerging evidence points to a fundamental role of the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPAR-γ) in modulating fibrogenesis. While PPAR-γ has long been known to be important in lipid metabolism and in glucose homeostasis, its role in regulating mesenchymal cell biology and its association with pathological fibrosis had not been appreciated until recently. This article highlights recent studies revealing a consistent association of fibrosis with aberrant PPAR-γ expression and activity in various forms of human fibrosis and in rodent models, and reviews studies linking genetic manipulation of the PPAR-γ pathway in rodents and fibrosis. We survey the broad range of anti-fibrotic activities associated with PPAR-γ and the underlying mechanisms. We also summarize the emerging data linking PPAR-γ dysfunction and pulmonary arterial hypertension (PAH), which together with fibrosis is responsible for the mortality in patients in SSc. Finally, we consider current and potential future strategies for targeting PPAR-γ activity or expression as a therapy for controlling fibrosis.

Keywords: PPAR-γ; SPPARM; TGF-β.; systemic sclerosis.

Fig. (1)

Structure of the human PPARγ gene and protein. (Upper panel, gene structure) Expression of PPAR-γ involves differential promoter usage, and the relative positions of the four known PPAR-γ promoters are designated as Pγ1-Pγ4. The transcript variants γ1, γ3, and γ4 encode the PPAR-γ1 isoform. Exon B (blue box) encodes the 28 additional amino acids found at the amino terminus of human PPAR-γ2 (30 amino acids in mouse PPAR-γ2). Exons 1–6 (yellow boxes) are common in all PPAR-γ1 transcripts and when they are spliced to exon B encode full-length PPAR-γ2. The sizes of the exon boxes approximate the relative lengths of each exon; however, the introns (depicted as straight lines) are not drawn to scale. (Lower panel, protein structure) The hypervariable A/B domain (red box) contains the activation function-1 (AF-1) domain. Human PPAR-γ2 contains a 28 amino acid amino terminal region. The C-domain (blue) contains the DNA binding domain (DBD). The D domain (hinge region, pink box) allows for conformational change following ligand binding to promote coregulator (coactivator or corepressor) docking. The E/F region (green box) contains the ligand binding domain (LBD) of PPAR-γ and the activation function-2 (AF-2) domain. PPAR-γ can be phosphorylated by MAP kinases at S112 or by CDK5 at S273. The AF2 domain participates in ubiquitin-dependent degradation and is necessary for full ligand-induced PPAR-γ transcriptional activity.

Fig. (2)

Model for ligand-induced PPAR-γ activation. In the absence of ligand, the PPAR/RXR heterodimer is bound to transcriptional co-repressors, which prevent its binding to PPRE. Upon ligand activation, PPARs undergo conformational change, and recruit co-activators such as p300/CBP and p160 to displace co-repressors, resulting in binding of target gene PPRE and inducing transcription.

Fig. (3)

A novel mechanism for PPAR-γ signaling? Obesity and high fat diet induce inflammation and cleavage of the p35 protein to generate p25. The p25 activates CDK5, which phosphorylates PPARγ on S273, thereby preventing the transcription of specific PPAR-γ targets (A, red box). The thiazolidinediones activate the full repertoire of PPARγ target genes via binding to the LBD. SPPARMs have positive effects (green) via blocking CDK5 and stimulating a discrete number of PPAR-γ responses (A, red box) through binding to LBD.

Fig. (4)

Fibrosis is associated with lipoatrophy. Skin biopsies demonstrating the association of dermal fibrosis with loss of the subjacent adipose tissue (adipose atrophy). A. SSc skin biopsy. Note dense dermal fibrosis and loss of subcutaneous fat. *, invasion of fibrotic tissue in adipose tissue. H&E stain, original magnification x 25. B. Skin biopsy from mouse with bleomycin-induced scleroderma. Note dense dermal fibrosis and absence of subcutaneous fat. Masson’s trichrome staining, original magnification x 100 (upper panel), 400 (lower panel).

Fig. (5)

Anti-TGF-β-induced profibrotic effects of PPAR-γ ligands. TGF-β induces cell proliferation, migration, fibroblast activation, and mesenchymal transition from epithelial cells, endothelial cells, and adipocytes. All these processes contribute to fibrosis formation and progression. PPAR-γ ligands have been shown to inhibit these processes in a variety of cell types. And there is reciprocal regulation between TGF-β signaling and PPAR-γ axis. TGF-β suppresses PPAR-γ expression, which might contribute to persistent activation of TGF-β signaling; PPAR-γ ligands, through PPAR-γ-dependent and –independent mechanism, abrogate TGF-β signaling and might have therapeutic potential in fibrosis.