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.