Prezentacja programu PowerPoint - biotka.mol.uj.edu.plbiotka.mol.uj.edu.pl/zbm/handouts/2007_09_receptors.pdf•Peroxisomes typically contain catalase, an enzyme that uses H 2 O 2

PPARPPAR

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PPAR PPAR –– history of researchhistory of research

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liver, brown adipocytes,kidney, heart, skeletal muscles, macrophages,

foam cells

ubiquitously expressed

adipocytes, intestine,retina, macrophages, foam

cells, endothelium

PPARPPARαα,, PPARPPARγγ,, PPARPPARδδ

-- LipidLipid--activated transcription activated transcription factorsfactors

-- RegulateRegulate::

** lipidlipid metabolismmetabolism

** glucose homeostasisglucose homeostasis

-- ImpairedImpaired PPARPPAR activity is activity is believedbelieved toto leadlead toto dyslipidemia dyslipidemia andand insulininsulin resistanceresistance

LTB4

•• PPeroxisomes typicallyeroxisomes typically contain catalasecontain catalase,, an enzymean enzymethat uses that uses HH22OO22 to to oxidize formic acidoxidize formic acid,, alcoholsalcohols,, phenolsphenols,, and other substratesand other substrates. . Any Any remaining remaining HH22OO2 2 present in the cell is broken downpresent in the cell is broken down byby catalase into water and free catalase into water and free oxygen moleculesoxygen molecules. .

•• Peroxisomes are responsible Peroxisomes are responsible for for degradation of fatty acids and the catalysis of the degradation of fatty acids and the catalysis of the initial steps in the synthesis of phospholipidsinitial steps in the synthesis of phospholipids, , utilized in membrane formationutilized in membrane formation..

PeroxisomesPeroxisomes

peroxisomeperoxisome

proliferatorsproliferators

•• The ubiquitous organellesThe ubiquitous organelles,, delineateddelineated by a singleby a singlemembranemembrane, , containcontaininging enzymes that utilize oxygenenzymes that utilize oxygen to to subtrasubtracct hydrogen atoms from organic substrates in t hydrogen atoms from organic substrates in an oxidative reaction that generates hydrogen an oxidative reaction that generates hydrogen peroxideperoxide. .

•• Peroxisome proliferators arePeroxisome proliferators are aa diverse diverse group of chemicalsgroup of chemicals. .

•• Responses of rodent hepatocytesResponses of rodent hepatocytes totoperoxisome proliferators include proliferaperoxisome proliferators include prolifera--tion of peroxisomestion of peroxisomes, , increase in increase in ββ--oxidation oxidation of fatty acidsof fatty acids, , resulting from induction of resulting from induction of all enzymes in the peroxisomalall enzymes in the peroxisomal ββ--oxidation oxidation cascadecascade, , andand hepatomegalyhepatomegaly..

•• The peroxisome proliferatorThe peroxisome proliferator--response has response has gained considerable interest duegained considerable interest due toto its its association with metastatic hepatocellular association with metastatic hepatocellular carcinomas in rodentscarcinomas in rodents.. The mechanismThe mechanism isisnot not clear clear -- these compounds these compounds do notdo not bind bind directly anddirectly and do notdo not damagedamage DNA.DNA.

Peroxisome proliferatorsPeroxisome proliferators

•• PPARsPPARs were cloned in 1990 as transcription factors that mediate the ewere cloned in 1990 as transcription factors that mediate the effects of ffects of synthetic synthetic peroxisome proliferatorsperoxisome proliferators..

•• Since this time Since this time PPARsPPARs have been described in a wide variety have been described in a wide variety of species ranging from of species ranging from zebrafishzebrafish and and XenopusXenopus to mouse and to mouse and human. human.

•• The The ligandligand binding pocket of binding pocket of PPARsPPARs is much larger than that of other is much larger than that of other NRsNRs, with a , with a volume of 1300 volume of 1300 ÅÅ, of which the , of which the ligandligand occupies only about 30% to 40%. occupies only about 30% to 40%.

•• Overall, Overall, PPARsPPARs appear to have evolved as appear to have evolved as NRsNRs adapted for binding to multiple adapted for binding to multiple natural natural ligandsligands with relatively low affinity.with relatively low affinity.

•• The first PPRE was identified in the promoter of the The first PPRE was identified in the promoter of the acylacyl coenzymecoenzyme A (A (acylacyl--CoACoA) ) oxidaseoxidase gene, and then in a number of genes activated during gene, and then in a number of genes activated during adipocyteadipocyte differentiation differentiation or associated with lipid metabolism. or associated with lipid metabolism.

PPARsPPARs ((peroxisome proliferatorperoxisome proliferator--activated receptorsactivated receptors))

Xenopus laevisDanio regio

In In the liverthe liver, PPAR, PPARαα targetstargets form a form a comprehensivecomprehensive ensemble ensemble ofof genes which participates in many ifgenes which participates in many if not not allall aspectsaspects ofof lipidlipidcatabolismcatabolism. . It includesIt includes::

* * transport transport of fatty acids in the circulationof fatty acids in the circulation, ,

** their uptaketheir uptake byby the hepatocytesthe hepatocytes,,

** intracellular bindingintracellular binding byby fatty acid binding proteinsfatty acid binding proteins, ,

** activationactivation byby the acylthe acyl--CoA synthaseCoA synthase, ,

** ββ--oxidation in the peroxisome and mitochondriaoxidation in the peroxisome and mitochondria, ,

* * ωω--oxidation in the microsomesoxidation in the microsomes..

PPARPPARαα and and lipid lipid metabolismmetabolism

Ethanol inhibits PPAREthanol inhibits PPARαα activityactivity –– it may playit may play a rolea role in in development of alcoholic fatty liverdevelopment of alcoholic fatty liver..

•• OverallOverall, PPAR, PPARαα actsacts as aas a globalglobal regulatorregulator of energy metabolismof energy metabolism,, which coordinates the which coordinates the rates of utilization of the various energy sources in relationrates of utilization of the various energy sources in relation toto food availabilityfood availability..

•• AccordinglyAccordingly, PPAR, PPARαα nullnull micemice which are viable andwhich are viable and do notdo not exhibit any obvious exhibit any obvious phenotype when kept under normal laboratory phenotype when kept under normal laboratory conditionsconditions andand diet, diet, experience serious experience serious difficulties during fastingdifficulties during fasting, a, a situation that normally results in an enhanced fatty acid situation that normally results in an enhanced fatty acid mobilization and increasedmobilization and increased ββ--oxidation in the liveroxidation in the liver asas fatty acids fatty acids representrepresent thethe majormajorenergy sourceenergy source. .

PPARPPARαα--//-- micemice

•• ConfrontedConfronted toto suchsuch aa metabolic challengemetabolic challenge, , PPARPPARαα nullnull micemice areare notnot capable of enhanced capable of enhanced fatty oxidation and rapidly suffer from fatty oxidation and rapidly suffer from hypoglycemiahypoglycemia and and hypothermiahypothermia..

•• With age they dWith age they develope obesityevelope obesity..

•• Mice Mice display increased inflammatory reactions display increased inflammatory reactions and delayed wound healingand delayed wound healing..

PPARα participates in the control of the inflammatory response:

* it decreases inflammation possibly via stimulation of catabolism of the proinflammatory lipid mediators.

* its activation results in repression of NFκB signaling which leads to decreased production of proinflam-matory cytokines in different cell-types.

Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation

Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

HDLHDLLDLLDLChylomicronsChylomicrons,,VLDL, and VLDL, and

their catabolic their catabolic remnantsremnants

> 30 nm> 30 nm 2020––22 nm22 nm

Potentially Potentially proinflammatoryproinflammatory

99––15 nm15 nmPotentially antiPotentially anti--

inflammatoryinflammatory

PPARα lowers trigliceride levels as a result of:- enhanced lipolysis, induction of FA uptake and catabolism- reduced FA synthesis and VLDL production by the liver- increased removal of LDL

Effect of dyslipidemiaEffect of dyslipidemia

Eruptive xanthomasEruptive xanthomas

Effect of dyslipidemia

Atherosclerotic plaquesAtherosclerotic plaques

healthy vesselhealthy vessel ~70% ~70% lumen reductionlumen reduction occlusiveocclusive plaqueplaque

hemorrhage

hemorrhagecalcification

Atherosclerosis Atherosclerosis is an Inflammatory Diseaseis an Inflammatory Disease

EndotheliumEndothelium

Vessel LumenVessel Lumen

IntimaIntima

Ross R. N Engl J Med 1999;340:115-126.

Foam CellFoam Cell

MonocyteMonocyte

CytokinesCytokines

Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinases

Cell ProliferationCell ProliferationMatrix DegradationMatrix Degradation MacrophageMacrophage

Role of LDL in InflammationRole of LDL in Inflammation


Vessel LumenVessel LumenLDLLDL

Steinberg D et al. N Engl J Med 1989;320:915-924.

LDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be Modified

LDLLDL

IntimaIntima

Modified LDLModified LDL

Modified LDL are Modified LDL are ProinflammatoryProinflammatory

Hydrolysis of Hydrolysis of PhosphatidylcholinePhosphatidylcholineto to LysophosphatidylcholineLysophosphatidylcholine

Other Chemical ModificationsOther Chemical Modifications

Oxidation of LipidsOxidation of Lipidsand and ApoBApoB

AggregationAggregation

LDLLDL

LDLLDL

Modified LDL Modified LDL sstimulatetimulate eexpressionxpression of MCPof MCP--1 in 1 in eendothelialndothelial ccellsells



IntimaIntima

MonocyteMonocyte

Navab M et al. J Clin Invest 1991;88:2039-2046.


MCPMCP--11

LDLLDL

LDLLDL

Differentiation of Differentiation of mmonocytesonocytes into into mmacrophagesacrophages



IntimaIntima

MonocyteMonocyte



Modified LDL PromoteModified LDL PromoteDifferentiation ofDifferentiation ofMonocytesMonocytes intointoMacrophagesMacrophages

MCPMCP--11

MacrophageMacrophage

LDLLDL

LDLLDLEndotheliumEndothelium

Vessel LumenVessel LumenMonocyteMonocyte


MCPMCP--11

AdhesionAdhesionMoleculesMolecules


Macrophages Macrophages eexpressxpress rreceptorseceptors tthat hat ttakeake up up mmodifiedodified LDLLDL

Foam CellFoam Cell

Modified LDL Modified LDL Taken up by Taken up by MacrophageMacrophage

IntimaIntima

LDLLDL

LDLLDL

Modified LDL Modified LDL iinducesnduces mmacrophagesacrophages to to rreleaseelease ccytokinesytokines tthat hat sstimulatetimulate aadhesiondhesion mmoleculeolecule eexpressionxpression in in eendothelialndothelial ccellsells



Nathan CF. J Clin Invest 1987;79:319-326.



MCPMCP--11

AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

IntimaIntima

LDLLDL

LDLLDLEndotheliumEndothelium


Mackness MI et al. Biochem J 1993;294:829-834.



MCPMCP--11AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

Foam Foam CellCell

HDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxIntimaIntima

HDL InhibitHDL InhibitOxidationOxidation

of LDLof LDL

HDL HDL ppreventrevent fformationormation of of ffoamoam ccellsells, , reducedreduced adhesionadhesionmoleculesmolecules andand iinhibitnhibit the the ooxidativexidative mmodificationodification of LDLof LDL

MechanismsMechanisms by by whichwhich fibratesfibrates increaseincrease HDL HDL levelslevels::-- transcriptionaltranscriptional inductioninduction ofof synthesissynthesis ofof thethe major HDL major HDL apolipoproteinsapolipoproteins ((apoAapoA--II andand apoAapoA--IIII) as ) as wellwellas as lipoproteinlipoprotein lipaselipase. . -- decreasedecrease inin hepatichepatic apoCapoC--IIIIII transcriptiontranscription andand enhancedenhanced clearanceclearance ofof triglyceridetriglyceride--richrich lipoproteinslipoproteins..

http://www.lipidsonline.org/slides/slide01.cfm?q=ppar&pg=1

PPARPPARαα and and atheroscleroatherosclero

sissis

Levebvre et al. 2006

http://www.lipidsonline.org/slides/slide01.cfm?q=fibrates&pg=2

MI MI –– myocardialmyocardial ubfarctionubfarction, CVA , CVA -- cerebrovascularcerebrovascular accidentaccident ((strokestroke), CHD ), CHD –– coronarycoronary heartheart diseasedisease

ProbabilityProbability ofof myocardialmyocardial infarctioninfarction duringduring 10 10 yearsyears

TreatmentTreatment withwith fibratesfibrates reducesreduces cardiovascularcardiovascular riskrisk

death or myocardial infarction

P=0.006

oxLDL

11 22 33 44 55 66

11 22 33 44 55 66

11 22 33 44 55 66

BB

NN

NN

NN

CC

CC

CC

PPARPPARγγ11

PPARPPARγ2γ2

PPARPPARγ3γ3

ExonExon A1A1 ExonExon A2A2 ExonExon BB ExonsExons 11--66

γγ11 γ3γ3 γ2γ2

proteinprotein

PPARPPARγγ genegene

Adipocyte differentiationAdiponectin

TNFα productionIL-6 production

Resistin production

Gluconeogenesis

VLDL synthesis

Glucose uptake

FatFatFat

LiverLiver

MuscleMuscle

PPARPPARγγ

PPARPPARγγ

PPARPPARγγ

Actions of PPARγ in adipocyte FA trapping Semple et al. 2006

MyeloidMyeloid precursorprecursor cellscells RestingResting monocytesmonocytes

LipidLipid--accumulatingaccumulatingmacrophagesmacrophages

CD36CD36oxLDLoxLDL uptakeuptake

TNFTNFααILIL--11ββILIL--66iNOSiNOSSRSR--AAMMPMMP--99

PPARγ

PPARγ

PGDPGD22PGJPGJ22

PPARPPARγγ--RXRRXRligandsligands

ActivatedActivatedmacrophagesmacrophages

EffectsEffects of of PPARPPARγγ on on thethe differentiationdifferentiation and and functionfunctionof of cellscells of of monocytemonocyte lineagelineage

After After KlieverKliever and and WillsonWillson 1998;1998;CurrentCurrent OpinionOpinion in in GeneticsGenetics and and DevelopmentDevelopment 8: 576.8: 576.

IFNIFNγγ

PPARPPARγγ−−RXRRXRligandsligands

ThiazolidinedionsThiazolidinedions (TZD):(TZD):pharmacologicalpharmacological activatorsactivators ofof PPARPPARγγ

In In clinicalclinical useuse

PPARPPARγγ –– role role inin tumorigenesistumorigenesis

-- HeterozygousHeterozygous mice mice withoutwithout one allele one allele ofofPPARPPARγγ treatedtreated withwith carcinogen carcinogen moremore oftenoftensuffersuffer fromfrom colon colon cancercancer thanthan normalnormal micemice..

-- HeterosomatHeterosomaticic mutamutationstions ofof PPARPPARγγ areare foundfoundinin 10%10% patientspatients withwith colon colon cancercancer, , andand eveneven inin40% 40% patientspatients withwith prostateprostate cancercancer ((mutationmutation ininthethe cancercancer cellscells)).. TheseThese mutationsmutations resultsresults inin thethelostlost ofof functionfunction ofof PPARPPARγγ..

PPARPPARγγ-- LigandsLigands ofof PPARPPARγγ inhibitinhibit proliferationproliferation andand induceinduceapoptosisapoptosis inin many many cellcell typestypes, , bothboth tumor tumor andand normalnormal..

-- LigandLigandss ofof PPARPPARγγ maymay induceinduce differentiationdifferentiation inin breastbreastcancercancer, colon , colon cancercancer, , lunglung cancercancer, , liposarcomaliposarcoma andandosteosarcomaosteosarcoma, , atat leastleast inin cellcell lineslines inin vitrovitro..

OOsteosarcomasteosarcomaLiposarcomaLiposarcoma

-- OsteosarOsteosarcomacoma isis thethe most most oftenoften cancercancer ofof bonesbones, , devolopingdevoloping usuallyusually inin humanshumans inin thethesecondsecond decadedecade ofof lifelife. . ItIt isis a a veryvery aggressiveaggressive tumor tumor whichwhich easilyeasily formsforms metastasesmetastases. . TheseThesemetastasesmetastases areare thethe most most commoncommon causecause ofof patientspatients’’ deathdeath. . TheyThey areare difficultdifficult for for diagnosisdiagnosisandand veryvery resistantresistant ((eveneven completelycompletely) to ) to conventionalconventional chemotherapieschemotherapies..

-- BothBoth osteoblastsosteoblasts andand adipocytesadipocytes originsorigins fromfrom thethe same same progenitorprogenitor cellscells inin bonebone morrowmorrowstroma. stroma. PerhapsPerhaps, , activationactivation ofof PPARPPARγγ maymay leadlead to to inductioninduction ofof differentiationdifferentiation ofof cellcellosteosarcomaosteosarcoma..

-- In In cellcell lineslines ofof humanhuman osteosarcomaosteosarcoma PPARPPARγγ isis expressedexpressed. .

-- TroglitazoneTroglitazone andand cciiglitazonglitazonee inhibitinhibit proliferationproliferation ofof thosethose cellcell lineslines, , induceinducedifferentiationdifferentiation andand induceinduce apoptosisapoptosis..

PPARPPARγγ -- osteosarcomaosteosarcoma

vehiclevehicle

ciglitazoneciglitazone

CiglitazoneCiglitazone ((PPARPPARγγ ligand) ligand) inhibitsinhibits proliferationproliferation andandincreasesincreases differentiationdifferentiation inin humanhuman osteosarcomaosteosarcoma cellcell lineslines

•• DiabetesDiabetes mellitusmellitus isis a a chronicchronic diseasedisease characcharac--terizedterized byby eelevatedlevated bloodblood sugarssugars for for monthsmonths to to yearsyears. .

•• DiabetesDiabetes isis characterizedcharacterized by by eithereither: (1) : (1) ananinabilityinability ofof thethe pancreaspancreas to to produceproduce insulin insulin ((typetype 1 1 oror insulininsulin--dependent dependent diabetesdiabetes mellitusmellitus) ) oror anan inabilityinability ofof insulin to insulin to exertexert itsits normalnormalphysiologicalphysiological actionsactions ((typetype 2 2 oror nonnon--insulin insulin dependent dependent diabetesdiabetes). ).

•• OftenOften recognizedrecognized inin patientspatients byby excessiveexcessiveurinationurination, , thirstthirst, , weightweight lossloss andand//oror a a lacklack ofofenergyenergy. But . But diabetesdiabetes isis oftenoften silentsilent andand maymayexistexist for many for many yearsyears withoutwithout thethe individual'sindividual'snoticingnoticing itit. .

•• TTissuesissues andand organsorgans whichwhich areare vulnerablevulnerable to to thethe damagingdamaging effectseffects ofof chronicallychronically high high bloodbloodsugarsugar levelslevels areare thethe eyeeye, , kidneykidney, , nervesnerves andandbloodblood vesselsvessels. .

DiabetesDiabetes

AnAn insulininsulin--resistantresistant statestate isis thethe keykey phasephase ofof metabolicmetabolic syndromesyndrome--XX: :

* * WithWith preservedpreserved pancreaticpancreatic ββ cellscells andand insulin insulin hypersecretionhypersecretion whichwhichcancan compensatecompensate for insulin for insulin resistanceresistance..

**WithWith damagedamage ofof pancreaticpancreatic ββ cellscells leadingleading to to decreasedecrease ofof insulin insulin secretionsecretion andand to to hyperglycemiahyperglycemia (to (to typetype 2 2 diabetesdiabetes). ).

http://www.cardiab.com/content/2/1/4/figure/F1

No Data <4% 4%-6% 6%-8% 8%-10% >10%

Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286:10.

Diabetes Trends* Among Adults in the U.S.,(Includes Gestational Diabetes)

BRFSS, 1990,1995 and 20011990 1995

2001

AboutAbout 60 to 70 % 60 to 70 % ofof peoplepeople diagnoseddiagnosed withwithdiabetesdiabetes developdevelop nervenerve damagedamage, , knownknown as as diabeticdiabetic neuropathyneuropathy. .

NeuropathyNeuropathy developsdevelops slowlyslowly andand oftenoften timestimes a a person person isis unawareunaware thatthat theythey areare loosingloosingsensationsensation inin theirtheir extremitiesextremities..

Monofilament applied to the planter surface of the Monofilament applied to the planter surface of the foot to the point of bucklingfoot to the point of buckling -- ffailureailure of patient to of patient to sense this pressure indicates sense this pressure indicates neuropathyneuropathy

NonNon--healinghealing ulcersulcersinin patientspatients withwith diabetesdiabetes

FindingsFindingsatat firstfirst diagnosisdiagnosis

PrevalencePrevalence ofof retinopathyretinopathyinin diabeticdiabetic patientspatients

MultipleMultiple metabolicmetabolic defectsdefectscoexistcoexist inin typetype 2 2 diabetesdiabetes

-- insulin insulin resistanceresistance inin skeletalskeletalmusclemuscle, , adiposeadipose tissuetissue andand liverliver

-- impairedimpaired insulin insulin secretionsecretion


-- SulfonylureasSulfonylureas andand meglitinidesmeglitinidesstimulatestimulate pancreaticpancreatic ββ cellscells to to secretesecrete moremore insulininsulin


-- MetforminMetformin suppresssuppress hepatichepaticglucoseglucose productionproduction

-- No No effecteffect on insulin on insulin secretionsecretion


-- TZD TZD promotepromote peripheralperipheralglucoseglucose utilizationutilization

-- No No effecteffect on insulin on insulin secretionsecretion

-- PromotePromote differentiationdifferentiation ofofsmallersmaller, , insulininsulin--sensitivesensitiveadipocytesadipocytes

TZD TZD –– effecteffect ofof insulin insulin resistanceresistance

TZD TZD –– effecteffect on on neointimaneointima formationformation

•• PPARPPARββ is relatively poorly characterized. is relatively poorly characterized.

•• Its expression is rather ubiquitous, with varying Its expression is rather ubiquitous, with varying levels in different organs.levels in different organs.

•• Endogenous Endogenous ligandligand for PPARfor PPARδδ is is prostacyclinprostacyclin(PGI(PGI2). 2).

•• PPARPPARδδ seems to play a very important role in seems to play a very important role in implantation of embryo. implantation of embryo.

•• It was also implicated in It was also implicated in oligodendrocyteoligodendrocytematuration.maturation.

PPARPPARβ (β (PPARPPARδδ))

PPAR PPAR expressionexpression inin epidermisepidermis duringduring woundwound healinghealing

•• Recent studies have demonstrated an involvement of PPARRecent studies have demonstrated an involvement of PPARδδ in regulation of wound in regulation of wound healing. Its activationhealing. Its activation::

* * contributes to lipid biosynthesis in contributes to lipid biosynthesis in sebocytessebocytes and and keratinocyteskeratinocytes

* * ameliorates inflammatory responses in the skin. ameliorates inflammatory responses in the skin.

* * diminishes proliferation and accelerates differentiation of diminishes proliferation and accelerates differentiation of keratinocyteskeratinocytes

* * enhances enhances keratinocytekeratinocyte resistance to apoptotic signals. resistance to apoptotic signals.

•• Increased proliferation and death of Increased proliferation and death of keratinocyteskeratinocytes at the at the

edges of epidermal wounds in PPARedges of epidermal wounds in PPARδδ mutant mice mutant mice

most likely participate in the healing delay observed most likely participate in the healing delay observed

in these animals.in these animals.

PPARPPARβ β –– woundwound healinghealing

EffectEffect ofof PPARPPARββ deficiencydeficiency on on keratinocytekeratinocyte adhesionadhesion......

......andand inin vitrovitro woundwound healinghealing..

•• Some studies indicate, that activation of PPARSome studies indicate, that activation of PPARδδ may influence may influence atherogenesisatherogenesis, although , although the final output of its action is not known yet. the final output of its action is not known yet.

•• ArtificialArtificial, , selective selective ligandligand ofof PPARPPARδδ was reported to cause a dramatic rise in HDL was reported to cause a dramatic rise in HDL cholesterol, while lowering the levels of cholesterol, while lowering the levels of LDL LDL small dense lipoprotein, fasting small dense lipoprotein, fasting trigliceridestriglicerides, , and insulin. and insulin.

•• On the other hand, On the other hand, PPARPPARδδ, whose expression is increased during differentiation of , whose expression is increased during differentiation of macrophages, increases the expression of genes involved in lipidmacrophages, increases the expression of genes involved in lipid uptake and storage, what uptake and storage, what may promote the macrophage lipid accumulation and foam cell formmay promote the macrophage lipid accumulation and foam cell formationation..

PPARPPARβ β −− atherosclerosisatherosclerosis

http://www.brown.edu/Courses/Digital_Path/Heart/atherosclerosis.htm

PPARPPARββ overexpressingoverexpressing micemice

-- OverexpressionOverexpression ofof PPARPPARββ in adipose tissue specifically induces expression of genes in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which required for fatty acid oxidation and energy dissipation, which then leads to improved lipid then leads to improved lipid profiles and reduced adiposity. profiles and reduced adiposity.

-- Importantly, these animals are Importantly, these animals are completely resistant to obesity that is induced by a highcompletely resistant to obesity that is induced by a high--fat dietfat diet and by genetic predisposition. and by genetic predisposition.

-- As predicted, treatment of obese mice with a synthetic PPARAs predicted, treatment of obese mice with a synthetic PPARββ agonist depletes lipid agonist depletes lipid accumulation. In parallel, PPARaccumulation. In parallel, PPARββ--deficient mice challenged with a highdeficient mice challenged with a high--fat diet show fat diet show reduced energy and are prone to obesity. reduced energy and are prone to obesity. MaybeMaybe PPARPPARββ serves as a widespread regulator serves as a widespread regulator of fat burning and is a potential target in the treatment of obeof fat burning and is a potential target in the treatment of obesitysity..

-- The The Marathon MMarathon Miceice areare capable of continuous running capable of continuous running of up to twice the distance of a wildof up to twice the distance of a wild--type littermate. This is type littermate. This is achieved by targeted expression of an activated form ofachieved by targeted expression of an activated form ofPPARPPARββ in skeletal muscle, which resulted in a dramatic in skeletal muscle, which resulted in a dramatic increase in "increase in "nonfatiguingnonfatiguing" type I muscle fibers. " type I muscle fibers.

marathonmarathon mousemouse

MetachromaticMetachromatic staining of the staining of the plantarisplantaris muscle. Type I fibersmuscle. Type I fibers areare stained dark stained dark blue.blue.

Increased Oxidative Type I FibersIncreased Oxidative Type I Fibers in thein the PPARPPARδδ Transgenic

Wang et al. 2004

MTransgenic MSkeletal muscle fibers are generally classified as type ISkeletal muscle fibers are generally classified as type I oor type II fibers. r type II fibers.

Type I fibersType I fibers ((oxidativeoxidative/slow) /slow) are mitochondriaare mitochondria richrich and mainly use oxidative metabolism and mainly use oxidative metabolism for energyfor energy production, which provides a stable and longproduction, which provides a stable and long--lasting supplylasting supply of ATP, and thus of ATP, and thus are fatigueare fatigue--resistant. resistant.

Type IIType II ((glycolytic/fasglycolytic/fast) t) fibers comprisefibers comprise three subtypes, three subtypes, IIaIIa, , IIxIIx, and , and IIbIIb. Type . Type IIbIIb fibers fibers have the lowesthave the lowest levels of mitochondrial content and oxidative enzymes, relylevels of mitochondrial content and oxidative enzymes, rely on on glycolyticglycolyticmetabolism as a major energy source, and aremetabolism as a major energy source, and are susceptible to fatigue, while the oxidative susceptible to fatigue, while the oxidative and contractionand contraction functions of type functions of type IIaIIa and and IIxIIx lie between type I and lie between type I and IIbIIb

SkeletalSkeletal musclesmuscles in thein the PPARPPARδδTransgenic MiceTransgenic Mice

Muscles in transgenic miceMuscles in transgenic mice (TG) (TG) are redder than those in wildare redder than those in wild--typetype mice mice (WT)(WT)

Wang et al. 2004

EffectEffect ofof PPARPPARδδ overexpressionoverexpression on on obesityobesity

Body Body weightweight

AdiposeAdipose tissuetissue morphologymorphology

Wang et al. 2004

EffectEffect ofof pharmacologicalpharmacologicalactivationactivation ofof PPARPPARδδ on on obesityobesity

OldOld mice mice fedfed a a highhigh--fatfat dietdiet

Body Body weightweight

BloodBlood glucoseglucose levellevelafterafter glucoseglucose injectioninjection

Wang et al. 2004

Therapeutic targets of PPARTherapeutic targets of PPARδδ

Barish et al. 2006

Simplified overview of current understanding of the metabolic roles of the 3 PPAR isoforms

SempleSemple et al. 2006et al. 2006

WhatWhat wouldwould be be profitableprofitable to to rememberremember inin JuneJune::

-- ExpressionExpression patternpattern andand physiologicalphysiological role role ofof PPARsPPARs

-- CurrentCurrent andand potentialpotential usageusage ofof PPARPPARαα andand PPARPPARγγ ligand ligand inin thethe clinicclinic

-- PotentialPotential clinicalclinical significancesignificance ofof PPARPPARββ

ThankThank youyou andand seesee youyou nextnext weekweek......

SSlideslides cancan be be foundfound inin thethe librarylibrary andand atat thetheHemeHeme OxygenaseOxygenase Fan Fan ClubClub pagepage::

https://https://biotka.mol.uj.edu.pl/~hemeoxygenasebiotka.mol.uj.edu.pl/~hemeoxygenase

Documents

Prezentacja programu PowerPoint - biotka.mol.uj.edu.plbiotka.mol.uj.edu.pl/zbm/handouts/2007_09_receptors.pdf•Peroxisomes typically contain catalase, an enzyme that uses H 2 O 2