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. 2011 Oct 12;111(10):6321-40.
doi: 10.1021/cr2001355.

PPARs and lipid ligands in inflammation and metabolism

Gregory S Harmon  1 , Michael T Lam, Christopher K Glass
Affiliations

PPARs and lipid ligands in inflammation and metabolism

Gregory S Harmon et al. Chem Rev. .
No abstract available

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Figures

Figure 1
Figure 1
PPAR transcriptional regulation and the production of endogenous ligands. A) Endogenous lipid ligand precursors undergo enzymatic conversion to active lipids, leading to their binding to PPAR/RXR heterodimers on target genes and recruitment of co-activator complexes that activate transcription. B) Cell-specific PPAR activation is regulated by the expression of metabolizing enzymes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expressed in colonic epithelial cells and prostaglandin D2 synthase (PGD2S) in macrophages, leading to the production of endogenous ligands 15-keto-prostaglandin E2 and 15-deoxy-Δ,-prostaglandin J2 respectively.
Figure 2
Figure 2
Transcriptional activation and repression by PPARs. A) In the absence of agonist ligand, co-repressor complexes bind to PPAR/RXR heterodimers on response elements in target gene enhancers and promoters, inhibiting gene expression. Upon agonist binding, corepressor complexes dissociate and co-activator complexes are recruited, resulting in transcriptional activation of target genes. B) Transrepression of NFκB and AP-1 target genes by direct interactions of PPARs with NFκB and/or AP-1 proteins. Such interactions may prevent coactivator recruitement required for transcriptional activation. C) PPAR inhibition of AP-1-dependent gene expression by inhibition of c-Jun N-terminal kinase (JNK) activity required for activation of AP-1 target genes. D) PPAR inhibition of inflammatory response genes by competition for commonly used, rate-limiting coactivators. E) PPARγ repression of inflammatory response genes by inhibition of NCoR clearance. Ligand induced SUMOylation of PPAR-γ results in its docking to NCoR-containing co-repressor complexes bound to AP-1 elements via non-phosphorylated cJun. This interaction inhibits signal-dependent turnover of NCoR complexes required for transcriptional activation. Repression mechanisms may operate in a cell-specific and in some cases gene specific manner. The relative importance of specific mechanisms has not been established in vivo.
Figure 3
Figure 3
Natural and synthetic PPAR-γ ligands. PPAR-γ ligands include the synthetic agonist BRL49653, the endogenous agonists 15-deoxy-Δ,-prostaglandin J2 (15d-PGJ2), 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE), and 15-keto-prostaglandin E2, and the endogenous antagonist 1-acyl-2,3-cyclic-glycerophosphate.
Figure 4
Figure 4
Natural and synthetic PPAR-α ligands. PPAR-α ligands include the synthetic agonist Wy14,643 and the endogenous agonist 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine.
Figure 5
Figure 5
Natural and synthetic PPAR-δ ligands. PPAR-δ ligands include the synthetic agonist GW2433 and the endogenous agonists 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE) and 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid (EPA).
Figure 6
Figure 6
Biosynthetic pathways leading to generation of some of the naturally occurring PPAR ligands. A. Ligands generated from arachidonic acid. B. Ligands generated from linoleic acid.
See this image and copyright information in PMC

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