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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.
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References

    1. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P. Cell. 1995;83:835. - PMC - PubMed
    1. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Proc. Natl. Acad. Sci. U.S.A. 1994;91:7355. - PMC - PubMed
    1. Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA. Endocrinology. 1994;135:798. - PubMed
    1. Forman BM, Chen J, Evans RM. Proc. Natl. Acad. Sci. U.S.A. 1997;94:4312. - PMC - PubMed
    1. Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT. Annu Rev Physiol. 2007;69:201. - PubMed

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