PHGY 210 Lecture Notes - Lecture 8: Peroxisome Proliferator-Activated Receptor Alpha, Oxysterol, Peroxisome Proliferator-Activated Receptor

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20 Jul 2016
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!the%immune%cells%sensed%an%infection%and%it%upped%1%hydroxyls%enzyme%to%up%vit%DN%you%can%
produce%your%own%antibiotics%in%the%form%of%peptides.%when%you%stimulate%the%receptors%for%
1%hyrdroxy%enzyme,%you%produced%2%of%these%peptides.%%
!PXR%ligands%and%drugN%drug%interactionsN%One%of%the%interesting%aspects%of%studies%of%PXR%
was%that%previous%classical%pharmacological%studies%had%shown%that%different%classes%of%
drugs%differed%in%their%capacity%to%induce%CYP3A%activity%in%mouse%and%humans.%Strikingly,%
these%differences%paralleled%exactly%the%relative%capacities%of%these%drugs%to%stimulate%the%
activity%of%human%and%mouse%PXRs.%These%studies%have%provided%researchers%in%the%
pharmacology%industry%with%avery%simple%screen%(i.e.%binding%to%and%activation%of%PXR)%to%
rapidly%assess%the%capacity%of%small%molecule%drug%candidates%to%activate%their%own%
metabolism%and%the%metabolism%of%other%drugs%(i.e.%drugNdrug%interactions).%Candidate%
compounds%that%are%potent%activators%of%PXRs%are%eliminated%from%further%drug%
development.%
!PPARsN%Control%of%lipid%metabolism%and%adipogenesis.%
o!N3%PPAR%receptors,%a,%d,%and%g.%Focus%on%PPAR%a%and%g%N%best%characterized%and%most%
interesting.%
o!Unfortunate%name%PPAR%(peroxisomal%proliferatorNactived%receptor)%derived%from%
observation%that%PPARs%bind%at%high%concentrations%classes%of%toxic%compounds%that%
caused%proliferation%of%peroxisomes%in%livers%of%rats%(apparently%the%same%
phenomenon%is%not%observed%in%humans,%but%the%compounds%are%toxic%anyway).%
!PPARa%
o!Most%highly%expressed%in%tissues%that%display%high%rates%of%fatty%acid%metabolism.%
o!Subsequent%to%discovery%that%PPARa%bound%peroxisomal%proliferators,%it%was%
discovered%that%PPARa%bound%certain%types%of%fatty%acids%and%their%metabolites%
o!More%recently,%shown%that%ligandNactivated%PPARa%receptors%stimulated%expression%of%
several%genes%controlling%fatty%acid%metabolism.%Thus,%some%fatty%acids%can%control%
their%own%metabolism%through%PPARa%by%inducing%the%expression%of%genes%encoding%
metabolic%enzymes%required%for%fatty%acid%catabolism.%
!PPARg%
o!One%of%the%most%fascinating%of%all%orphan%receptors.%
o!Most%highly%expressed%in%adipose%tissue%intestine%and%spleen.%
o!First%high%affinity%ligand%for%PPARg%was%identified%in%a%large%ligand%screen%at%GlaxoN
Wellcome,%and%turned%out%to%be%a%thiazolidinedione%(TZD)%
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