PPARs Mediate Lipid Signaling in Inflammation and Cancer

Figure 1

PPARs are mediators of lipid signaling in inflammation and cancer. Lipid mediators originate from and participate in the control of physiological and pathophysiological situations. Many lipid-modifying enzymes are involved in the production of PPAR ligands. The cyclooxygenases (COX), lipoxygenases (LO), epoxygenases/cytochrome (CYP)/P450s enzymes, and the lipases use either fatty acids, triglycerides, or phospholipids as substrates to generate PPAR ligands, which are guided to their receptors by the cytoplasmic fatty acid binding proteins (FABPs). PPARs translate these lipid signals into responses, which maintain energy homeostasis, regulate inflammation and modify tumor growth. Among the pathways involved in inflammation and cancer, PPARs interact with COX2, NF-κB, MAPKs, and PTEN. PPARα and γinhibit COX2 expression, thereby reducing the production of their own ligands. Conversely, PPARβ/δ is thought to activate COX2 expression, generating a positive feedback loop by increasing the production of PPAR ligands. PPARs reduce inflammation by inhibiting NF-κB, a major pathway that links chronic inflammation to cancer promotion. Several modes of interactions between PPARs and MAPKs have been reported, but the relevance and consequences of such crosstalks are unclear. Finally, PPARβ/δ and γdecrease and increase the expression of the tumor suppressor PTEN (phosphatase and tensin homologue deleted from chromosome 10), respectively. PPARγ activation of PTEN is thought to potentiate its tumor suppressor function, whereas PPARβ/δ would have the opposite effect.