Peroxisome Proliferator-Activated Receptors: Difference between revisions
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==Biological Role== | ==Biological Role== | ||
[[Image: PPAR_Mechanism.png|500px|left|thumb| PPAR Mechanism of Action in the Human Body]] | [[Image: PPAR_Mechanism.png|500px|left|thumb| PPAR Mechanism of Action in the Human Body]] | ||
Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific [[DNA]] binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα, and bind to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes, repressing transcription. <ref>PMID:11330046</ref> Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity, enforcing a tight chromatin structure which prevents gene transcription. <ref>PMID:15681609</ref> This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited to the scene. These protein complexes modulate chromatin remodeling and facilitate DNA unwinding and linkage to RNA polymerase II machinery to commence transcription. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), <ref> pmid:7539101</ref>, PGC-1 (Recruit [http://en.wikipedia.org/wiki/Histone_acetyltransferase HAT activities]), | Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific [[DNA]] binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα, and bind to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes, repressing transcription. <ref>PMID:11330046</ref> Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity, enforcing a tight chromatin structure which prevents gene transcription. <ref>PMID:15681609</ref> This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited to the scene. These protein complexes modulate chromatin remodeling and facilitate DNA unwinding and linkage to RNA polymerase II machinery to commence transcription. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), <ref> pmid:7539101</ref>, PGC-1 (Recruit [http://en.wikipedia.org/wiki/Histone_acetyltransferase HAT activities]), PRIC-285,320 (Chromatin Remodeling via Helicase activity)<ref>PMID:11158331</ref>and PIMT (RNA Capping via methyltransferase activity)<ref>PMID:10381882</ref>. | ||
PPARs regulate diverse biological processes varying from lipid and carbohydrate metabolism to inflammation and wound healing. While PPARα is the major regulator of fatty acid oxidation and uptake in the liver, PPARγ is expressed at extremely high levels in adipose tissue, macrophages, and the large intestine and controls lipid [http://en.wikipedia.org/wiki/Adipogenesis adipogenesis] and energy conversion. PPARδ is expressed in most tissues and plays diverse roles involved in metabolism and wound healing. These nuclear receptors are of critical importance to the body as exemplified by PPARα knockdown mice suffering from a variety of metabolic defects including [http://en.wikipedia.org/wiki/Hypothermia hypothermia], elevated plasma free fatty acid levels, and [http://en.wikipedia.org/wiki/Hypoglycemia hypoglycemia], ultimately leading to death.<ref> PMID:10377439</ref> | PPARs regulate diverse biological processes varying from lipid and carbohydrate metabolism to inflammation and wound healing. While PPARα is the major regulator of fatty acid oxidation and uptake in the liver, PPARγ is expressed at extremely high levels in adipose tissue, macrophages, and the large intestine and controls lipid [http://en.wikipedia.org/wiki/Adipogenesis adipogenesis] and energy conversion. PPARδ is expressed in most tissues and plays diverse roles involved in metabolism and wound healing. These nuclear receptors are of critical importance to the body as exemplified by PPARα knockdown mice suffering from a variety of metabolic defects including [http://en.wikipedia.org/wiki/Hypothermia hypothermia], elevated plasma free fatty acid levels, and [http://en.wikipedia.org/wiki/Hypoglycemia hypoglycemia], ultimately leading to death.<ref> PMID:10377439</ref> | ||