Peroxisome Proliferator-Activated Receptor-Targeted Therapies: Challenges upon Infectious Diseases

Abstract

Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents.

Keywords: bacteria; infection; parasite; peroxisome proliferator-activated receptor; virus.

Figure 1

Roles of peroxisome proliferator-activated receptors (PPARs) and their regulatory mechanisms. PPAR ligands bind to the PPAR ligand-binding domain and activate receptors. PPARs interact with heat shock protein (HSP) in the cytosol. PPARs inhibit inflammation-related gene transcription by interfering with transcription factors such as NF-κB, AP-1, STAT, and NFAT. PPARs form heterodimers with Retinoid X receptor (RXR), a receptor of 9-cis-retinoic acid (9-cis-RA), and bind to direct repeat 1 (DR-1), a peroxisome-proliferator-responsive element. The PPAR-RXR heterodimer complex and co-repressors represses target gene transcription. However, the complex with co-activators promotes target gene transcription. Through these mechanisms, PPARs play significant roles in energy metabolism, inflammatory modulation, and the cell cycle. AP-1, Activator protein 1; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT, Nuclear factor of activated T cells; STAT, Signal transducer and activator of transcription.