Peroxisome proliferator-activated receptors (PPARs) and ovarian function--implications for regulating steroidogenesis, differentiation, and tissue remodeling

Abstract

The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors involved in varied and diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism. These processes are critical for normal ovarian function, and all three PPAR family members--alpha, delta, and gamma, are expressed in the ovary. Most notably, the expression of PPARgamma is limited primarily to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH). Although much has been learned about the PPARs since their initial discovery, very little is known regarding their function in ovarian tissue. This review highlights what is known about the roles of PPARs in ovarian cells, and discusses potential mechanisms by which PPARs could influence ovarian function. Because PPARs are activated by drugs currently in clinical use (fibrates and thiazolidinediones), it is important to understand their role in the ovary, and how manipulation of their activity may impact ovarian physiology as well as ovarian pathology.

Figure 1

Structure, relationship and splice variants of the PPARs. A) Schematic diagram of the structure common to nuclear hormone receptors and the PPARs, indicating the relative similarities between the various regions of PPAR isotypes across species [4] [139] [140]. B) Schematic of the splice variants of the PPARs. Schematic of PPARα adapted from [7] [8] [141]. The diagram of PPARδ splice variants was adapted from [9]. Exons IA, IB, IC, ID, and 2 are non-coding. Regarding PPARγ splice variants, exons 1–6 are common to all PPARγ subtypes. PPARγ₁ includes the untranslated exons A1 and A2, PPARγ₂ contains the translated exon B, PPARγ₃ contains the untranslated exon A2, PPARγ₄ contains only exons 1–6 (adapted from [4] [10] [142]). Images not drawn to scale.

Figure 2

Mechanism of action of PPARs. PPARs heterodimerize with RXRs both in the presence and absence of ligand. After ligand binding, PPARs undergo conformational change resulting in dissociation of corepressors, and the binding of coactivators. PPAR/RXR heterodimers bind to a DR1 sequence in the promoter region of target genes (see text for details).

Figure 3

Localization of mRNAs corresponding to PPARα (A, B, C) and PPARδ (D, E, F) in ovarian tissue collected from immature rats 48 hours post-eCG. Tissue sections (8 μm) were hybridized with ³⁵S-labled antisense (A, D) and sense (C, F) riboprobes for each respective PPAR isotype. Figures originally published in [62].

Figure 4

Localization of mRNA and protein corresponding to PPARγ in ovarian tissue collected from immature rats 0 (A, E) and 48 (B, F) hours post-eCG, and 4 (C, G) and 24 hours (D, H) post-hCG. Frozen tissue sections (8 μm) were hybridized with an antisense riboprobe corresponding to PPARγ. Figures A – D originally published in [71]. Protein corresponding to PPARγ, identified by the brown reaction product, was localized in 4% paraformaldehyde-fixed, paraffin embedded tissue using an anti-PPARγ antibody (Santa Cruz).

Figure 5

Proposed mechanisms by which PPARs may impact ovarian function and female fertility. The flow chart illustrates the potential interactions between the activation of PPARs and various factors known to impact processes critical for normal ovarian function. See text for details. Stimulatory impact is indicated by a (+). The ability to both stimulate and/or inhibit is denoted by (+/-). COX-2 = cyclooxygenase 2; ET-1 = endothelin -1; LDL = low density lipoprotein; MMPs = matrix metalloproteinases; NOS = nitric oxide synthase; NSAIDs = non-steroidal anti-inflammatory drugs; PAI-1 = plasminogen activator inhibitor -1; VEGF = vascular endothelial growth factor. Asterisk (*) denotes reported targets of PPARs in the ovary.