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Clofibrate Causes an Upregulation of PPAR- Target Genes but Does Not

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tapraid4/zh6-areg/zh6-areg/zh600707/zh65828d07a xppws S� 1 4/20/07 9: 48 MS: R-00603-2006 Ini: 07/rgh/dh A " #h!si$l %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ 3. Originalarbeiten *irst publis#ed "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ Clofibrate causes an upregulation of PPAR-� target genes but does not alter AQ: 1 expression of SREBP target genes in liver and adipose tissue of pigs Sebastian Luci, Beatrice Giemsa, Holger Kluge, and Klaus Eder Institut fu¨r Agrar- und Erna¨hrungswissenschaften, Martin-Luther-Universita¨t Halle-Wittenberg, Halle (Saale), Ger an! Submitted 25 August 2006 accepted in final form ! "arc# 200! AQ: 2 Luci S, Giemsa B, Kluge H, Eder K. Clofibrate causes an usuall0 increased 3#en baseline concentrations are lo3 1?62$ upregulation of PPAR-� target genes but does not alter expression of Effects of PPAR-� activation #ave been mostl0 studied in SREBP target genes in liver and adipose tissue of pigs$ A " #h!si$l rodents) 3#ic# ex#ibit a strong expression of PPAR-� in liver %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ *irst publis#ed and s#o3 peroxisome proliferation in t#e liver in response to "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ ./#is stud0 inves- PPAR-� activation 1&62$ Expression of PPAR-� and sensitivit0 tigated t#e effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor 1PPAR2-� and various to peroxisomal induction b0 PPAR-� agonists) #o3ever) var0 genes of t#e lipid metabolism in liver and adipose tissue of pigs$ An greatl0 among species 1+ %) 2+ 2$ 7n contrast to rats and mice) experiment 3it# + 4 pigs 3as performed in 3#ic# pigs 3ere fed eit#er 3#ic# are #ig#l0 sensitive to induction b0 peroxisome prolif- a control diet or t#e same diet supplemented 3it# 5 g clofibrate,5g for erators) guinea pigs) mon5e0s) pigs) and #umans are relativel0 24 da0s$ Pigs treated 3it# clofibrate #ad #eavier livers) moderatel0 insensitive 12+ ) &2) &%) ?42$ 7n t#ese nonproliferating species) increased mR6A concentrations of various PPAR-� target genes in expression of PPAR-� in t#e liver is muc# lo3er and t#e liver and adipose tissue) a #ig#er concentration of &-#0drox0but0rate) response of man0 genes to PPAR-� activation is 3ea5er t#an and mar5edl0 lo3er concentrations of trigl0cerides and c#olesterol in in proliferating species 142$ plasma and lipoproteins t#an control pigs 1# � 0$ 052$ mR6A con- 7n contrast to rodents) t#ere is little information to date about centrations of sterol regulator0 element-binding proteins 1SREBP2-+ t#e effects of PPAR-� agonists on lipid metabolism in pigs) Insig -( Insig-) and -2) insulin-induced genes 1 2 and ) and t#e SREBP 3#ic# are not onl0 of agricultural importance but are also a target genes acet0l-CoA carbox0lase) &-met#0l-&-#0drox0glutar0l- CoA reductase) and lo3-densit0 lipoprotein receptor in liver and valuable model for stud0ing t#e lipid metabolism because of adipose tissue and mR6A concentrations of apolipoproteins A-7) A-77) t#eir close relations#ip to #umans 162$ 7t #as been s#o3n t#at AQ: 3 and C-777 in t#e liver 3ere not different bet3een bot# groups of pigs$ treatment of pigs 3it# clofibrate stimulates mitoc#ondrial and 7n conclusion) t#is stud0 s#o3s t#at clofibrate treatment activates peroxisomal � -oxidation in liver) muscle) and 5idne0 1&?) 562$ PPAR-� in liver and adipose tissue and #as a strong #0potrigl0ceri- "oreover) it 3as found t#at pigs express functional PPAR-� in demic and #0poc#olesterolemic effect in pigs$ /#e finding t#at mR6A t#e liver) and several target genes induced in t#e liver b0 concentrations of some proteins responsible for t#e #0polipidemic PPAR-� activation #ave been identified 142$ ;o3ever) effects action of fibrates in #umans 3ere not altered suggests t#at t#ere 3ere of PPAR-� activation on lipid concentrations in plasma and certain differences in t#e mode of action compared 3it# #umans$ 7t is liver of pigs #ave not 0et been investigated$ 7n contrast to rats) also s#o3n t#at PPAR-� activation b0 clofibrate does not affect mice) or #umans in 3#ic# PPAR-� is predominant in liver #epatic expression of SREBP target genes involved in s0nt#esis of 1+ + 2) pigs ex#ibit also a #ig# expression of PPAR-� in adipose trigl0cerides and c#olesterol #omeostasis in liver and adipose tissue of pigs$ tissue) and it #as been suggested t#at pigs #ave a considerable capacit0 for � -oxidation in adipose tissue 1+ &2$ /#e effect of peroxisome proliferator-activated receptor-� c#olesterol trigl0cer- PPAR-� agonists on gene expression of PPAR-� target genes AQ: 4 ides in adipose tissue of pigs) #o3ever) #as not 0et been investi- gated$ Recent studies 1+ !) 2&) 25) &&2 in rodents suggested t#at *7BRA/ES ARE A 8R9:P 9* ;<P9=7P7>E"7C agents t#at #ave been in activation of PPAR-� in@uences #epatic trigl0ceride s0nt#esis clinical use for several decades in #umans 1?62$ 7t is 3ell and c#olesterol #omeostasis b0 interacting 3it# gene expres- establis#ed t#at t#ese agents act as s0nt#etic agonists of per- sion or proteol0tic activation of sterol regulator0 element- oxisome proliferator-activating receptor-� 1PPAR-�2) a nu- binding proteins 1SREBPs2) 5e0 regulators of lipid s0nt#esis clear receptor also activated b0 natural ligands suc# as free and #omeostasis$ SREBP-+ preferentiall0 activates genes re- fatt0 acids or some eicosanoids$ PPAR-� is an important Auired for fatt0 acid s0nt#esis) 3#ereas SREBP-2 preferen- regulator of cellular fatt0 acid upta5e and intracellular fatt0 tiall0 activates t#e =>= receptor gene and various genes acid transport) mitoc#ondrial and peroxisomal fatt0 acid oxi- reAuired for c#olesterol s0nt#esis 1222$ SREBPs are s0nt#e- dation) 5etogenesis) and gluconeogenesis 1?42$ 7n #umans) t#e siBed as inactive precursors bound to t#e endoplasmatic retic- most pronounced effect of fibrates is a decrease in plasma ulum membranes$ *or activation to occur) membranes #ave to trigl0ceride-ric# lipoproteins$ Concentrations of lo3-densit0 be cleaved b0 t3o resident proteases 3it#in t#e 8olgi) 3#ic# AQ: 5 lipoprotein 1=>=2 c#olesterol generall0 decrease in individuals seAuentiall0 cleave t#e SREBPs and release t#e amino-terminal 3it# elevated baseline plasma concentrations) and plasma b;=;-Cip-containing domain from t#e membrane) allo3ing it #ig#-densit0 lipoprotein 1;>=2 c#olesterol concentrations are to translocate to t#e nucleus and activate transcription of target Address for reprint reAuests and ot#er correspondence' D$ Eder) 7nstitut fuEr Agrar- und ErnaE#rungs3issensc#aften) "artin-=ut#er-:niversitaEt ;alle- /#e costs of publication of t#is article 3ere defra0ed in part b0 t#e pa0ment Fittenberg) Emil-Abder#alden-Str$ 26) >-06+ 04 ;alle 1Saale2) 8erman0 of page c#arges$ /#e article must t#erefore be #ereb0 mar5ed Hadvertise entI AQ: 12 1e-mail' Dlaus$ ederG land3$ uni-#alle$ de2$ in accordance 3it# + 4 :$ S$ C$ Section + !&? solel0 to indicate t#is fact$ AQ: 12 #ttp' ,,333$ a-pregu$ org 0&6&-6+ + %,0! J4$ 00 Cop0rig#t K 200! t#e American P#0siological Societ0 R+ 16 tapraid4/zh6-areg/zh6-areg/zh600707/zh65828d07a xppws S� 1 4/20/07 9: 48 MS: R-00603-2006 Ini: 07/rgh/dh R2 E**EC/S 9* C=9*7BRA/E /REA/"E6/ 76 P78S genes$ 7nsulin-induced genes 1Insig2-( and Insig-) are modu- diet per da0$ /#e amount of diet administered 3as � + 5O belo3 t#at lators of SREBP activit0 15&) 552$ /#e0 bloc5 t#e proteol0tic consumed ad libitum b0 pigs of a similar 3eig#t 1as assessed in a cleavage and transcriptional activation of SREBP$ 7n pigs) in previous stud02$ /#erefore) t#e diet offered 3as completel0 ta5en in AQ: ( contrast to rodents in 3#ic# lipogenesis ta5es place primaril0 b0 all pigs in t#e experiment$ >uring t#e feeding period) t#e amount of diet offered eac# da0 3as increased continuousl0 from ?00 to + )200 g$ in t#e liver 1+ 5) ??2) adipose tissue is t#e ma-or site of /#e pigs #ad free access to 3ater via nipple drin5ing s0stems$ /#e lipogenesis$ 7t #as been s#o3n t#at SREBP-+ and its target experimental diets 3ere administered for 24 da0s$ All experimental gene fatt0 acid s0nt#ase) one of t#e 5e0 enB0mes of de novo procedures described follo3ed establis#ed guidelines for t#e care and fatt0 acid s0nt#esis) are expressed at a #ig#er level in pig use of laborator0 animals and 3ere approved b0 t#e local veterinar0 adipose tissue t#an in pig liver 1+ 2) + &2$ F#et#er a lin5 exists office$ AQ: ) also in pigs bet3een PPAR-� activation and gene expression or Sa 'le c$llecti$n* After completion of t#e feeding period) t#e proteol0tic activation of SREBPs in liver or adipose tissue) animals 3ere 5illed under lig#t anest#esia$ *our #ours before eut#a- 3#ic# in turn could in@uence lipid s0nt#esis) is presentl0 nasia) eac# pig 3as fed its respective diet$ After deat#) blood 3as un5no3n$ collected into #epariniBed pol0et#0lene tubes$ Plasma 3as obtained b0 /#e ob-ective of t#e present stud0 3as to investigate t#e centrifugation of t#e blood 1+ )+ 00 g at ?NC for + 0 min2$ Plasma effects of clofibrate treatment on expression of genes involved lipoproteins 3ere separated b0 step-3ise ultracentrifugation 1"i5ro- :ltraBentrifuge Sorvall Products) Bad ;omburg) 8erman02 at in lipid metabolism in liver and adipose tissue of pigs$ Fe 3ere %00)000 g at ?NC for + $ 5 #$ Plasma densities 3ere ad-usted b0 sodium particularl0 interested in to 3#at extent clofibrate upregulates c#loride and potassium bromide) and t#e lipoprotein fractions � � AQ: * PPAR-� target genes in liver and adipose tissue of pigs and + $ 006 5g,l Lver0 lo3-densit0 lipoproteins 1Q=>=2 plus c#0lomicronsM) 3#et#er t#ere is an interaction
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    A Service of Leibniz-Informationszentrum econstor Wirtschaft Leibniz Information Centre Make Your Publications Visible. zbw for Economics Kaiser, Ulrich; Mendez, Susan J.; Rønde, Thomas Working Paper Regulation of pharmaceutical prices: Evidence from a reference price reform in Denmark ZEW Discussion Papers, No. 10-062 Provided in Cooperation with: ZEW - Leibniz Centre for European Economic Research Suggested Citation: Kaiser, Ulrich; Mendez, Susan J.; Rønde, Thomas (2010) : Regulation of pharmaceutical prices: Evidence from a reference price reform in Denmark, ZEW Discussion Papers, No. 10-062, Zentrum für Europäische Wirtschaftsforschung (ZEW), Mannheim This Version is available at: http://hdl.handle.net/10419/41440 Standard-Nutzungsbedingungen: Terms of use: Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Documents in EconStor may be saved and copied for your Zwecken und zum Privatgebrauch gespeichert und kopiert werden. personal and scholarly purposes. Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle You are not to copy documents for public or commercial Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich purposes, to exhibit the documents publicly, to make them machen, vertreiben oder anderweitig nutzen. publicly available on the internet, or to distribute or otherwise use the documents in public. Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verfügung gestellt haben sollten, If the documents have been made available under an Open gelten abweichend von diesen Nutzungsbedingungen die in der dort Content Licence (especially Creative Commons Licences), you genannten Lizenz gewährten Nutzungsrechte. may exercise further usage rights as specified in the indicated licence. www.econstor.eu Dis cus si on Paper No. 10-062 Regulation of Pharmaceutical Prices: Evidence from a Reference Price Reform in Denmark Ulrich Kaiser, Susan J.