Uric Acid: A Danger Signal From the RNA World That MayHave a Role in the Epidemic of Obesity, MetabolicSyndrome, and Cardiorenal Disease: Evolutionary ConsiderationsRichard J. Johnson, MD,* Miguel A. Lanaspa, PhD,* and Eric A. Gaucher, PhDSummary:All humanbeingsareuricaseknockouts; welost theuricasegeneasaresult of amutationthatoccurredinthemid-Mioceneepochapproximately15millionyearsago. Theconsequenceof beingauricaseknockout is that we have higher serum uric acid levels that are less regulatable and can be readily inuenced bydiet. Thisincreasesour riskfor gout andkidneystones, but thereisalsoincreasingevidencethat uricacidincreases our risk for hypertension, kidney disease, obesity, and diabetes. This raises the question of why thismutation occurred. In this article we review current hypotheses. We suggest that uric acid is a danger and survivalsignal carried over from the RNA world. The mutation of uricase that occurred during the food shortage and globalcoolingthat occurredintheMioceneepochresultedinasurvival advantageforearlyprimates, particularlyinEurope. Today, thelossof uricasefunctionsasathriftygene, increasingourriskforobesityandcardiorenaldisease.Semin Nephrol 31:394-399 2011 Elsevier Inc. All rights reserved.Keywords: Uricase, fructose, thrifty gene, anti-oxidant, oxidant, RNA worldUric acid is a product of purine metabolism gen-eratedduringthe breakdownof nucleic acids(DNAand RNA) and adenosine triphosphate(ATP), and uric acid also can be generated from proteins.Inmost mammals uricacidis metabolizedfurther byuricase(urateoxidase) toform5-hydroxyisourateandlater allantoin, whichis excretedfreelyinthe urine.1However, the uricase gene became nonfunctional in twoprimatelineagesduringthemiddleMioceneepochap-proximately9and15millionyearsago,andasaresulthumanbeings, great apes, andlesser apeshavehigherserum uric acid levels that are also less regulatable thanfor other mammals.2Today,serumuricacidlevelsvarygreatlyinhumanbeings, andcanrangefrom2.5to12mg/dLor more.Patientswithhigherlevelsareatincreasedriskforde-velopinggout anduricacidkidneystones. Moreimpor-tantly, an increased uric acid level also predicts the devel-opment of obesity,3metabolicsyndromeanddiabetes,4fattyliver,5hypertension,6andcardiovascularandrenaldiseases.7,8Recent studies have suggested that uric acidmay have a participatory role in these latter conditions.9Thishasledtothekeyquestionofwhatthebiologicalbenets of uric acid are, and why the mutation wasnaturally selected for our species.PARALLEL MUTATIONS INTHE URICASE GENEThe Miocene epoch is famous for the introduction of theape, which is distinct from monkeys by their larger headandbodyandabsenceof tail. Therst apes, suchasProconsul, wereidentiedintheearlyMioceneepoch(approximately20-23millionyearsago)andwerelim-itedtoAfrica. Theseearlyapes livedintropical rainforests and subsisted almost entirely on fruits. Approxi-mately 17 to 18 million years ago global cooling resultedinaloweringoftheTethysseaandtheformationofalandbridgetoEurasia, andat this timetherst apesenteredEurope. As global coolingcontinuedtheapesliving in Europe began to face a food shortage as a resultof to the changing climate and ora, especially during theseasonal cooler periods. As such, these apes retreated toisolatedsites (refugia) throughout Europe. Incontrast,although global cooling also occurred in Africa, the ma-jor effect was a recession of the tropical forests, but theystill remainedsuchthat changes indiet were not re-quired.10As global cooling continued, the apes in Europe beganto show evidence of periodic starvation, as indicated bylinearstriationsonthecaninescausedbyenamel hyp-oplasia that has been shown to reect periods of starva-tion in young apes while the canines are still enlarging.11A binary asteroid impact also occurred in southern Ger-many 15 million years ago, which showered detritus forup to 450 km from the site of impact,12although it is ofuncertainsignicancebecauseitisnotthoughttohavealtered the ora or fauna in Europe signicantly. By 8 to*Division of Renal Diseases and Hypertension, University of ColoradoDenver, Aurora, Colorado.School of Biology, Georgia Institute of Technology, Atlanta, GA.Support for this article was provided by National Institutes of Healthgrant HL-68607. Richard Johnson and Miguel Lanaspa are listed asinventors onpatent applications todecrease uric acidor blockfructose metabolism as a means for treating obesity and metabolicsyndrome or related conditions.Address reprint requests toRichardJ. Johnson, Divisionof RenalDiseases and Hypertension, University of Colorado Denver, 12700E19th Ave, Room7015, Aurora, CO80045. E-mail: richard.johnson@ucdenver.edu0270-9295/ - see front matter 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.semnephrol.2011.08.002Seminars in Nephrology, Vol 31, No 5, September 2011, pp 394-399 3949 million years ago the progressive cooling in Europe ledto an extinction of ape species in Europe.13Studies basedonthe fossil recordsuggest that theEuropean apes have skeletal and dental features that aremore similar to modern great apes, and as such has led totheproposalthatsomeoftheEuropeanapesmayhavemigrated back to Africa before their extinction in Europe(theBacktoAfricahypothesis).14BothKenyapithecusand Dryopithecus have been considered potential candi-dates for being this ancestral species.14,15It was during this period of climatic upheaval that thesilencingof uricase occurredinthe ancestral ape forhuman beings and the great apes. There is evidence thatit occurredstepwise, rst withprogressivedecreaseinuricase activity as a result of mutations in the promoterregion, followedbycompletesilencingofuricaseasaresult of a mutation in codon 33 of exon 2, the latter hasbeendatedtoapproximately15.4millionyearsago.2Aseparatemutationinvolvingtheancestralapeforlesserapes(gibbonsandsiamangs) occurredincodon18ofexon 2 and has been dated to approximately 9.8 millionyears ago.2Some new world monkeys also may have hadindependent mutations in uricase, and the old worldmonkeys also show less uricase activity than many othermammals.16Therefore, there appears to be a generalselection pressure favoring a loss of uricase in this orderof mammals.We have hypothesized that the uricase mutation ben-etted survival by augmenting the fat-storing propertiesof fructose present in fruits.10We also have proposed thatthis mutation occurred in Europe because it would haveprovided a selection advantage here and would havetakenover thepopulationof ageographicallyisolatedrefugiarapidly. Wethereforehavesuggestedthat thismutationsupportstheBacktoAfricahypothesis.10Be-fore we discuss this hypothesis, however, we brieyreviewother theories for whythis mutationoccurred(Fig. 1).URIC ACIDANDWATER CONSERVATIONTheoriginalinterestintheevolutionaryroleofuricaserelated to studies of how nitrogenous waste products areexcreted in different species.17Some animals excretetheir nitrogenous wastes as ammonia, others as urea, andyetothersasuricacid.Reptilesandbirdscomposethislattergroupandfacilitatethisbyhavingamutationinuricase. Smith18suggested that this mutation was criticalfor reptiles andbirds sothat theycouldexcretetheirnitrogenouswastesasuricacid.Becauseuricacidcon-tains 4 nitrogens per molecule as compared with urea (2nitrogens/molecule) and ammonia (1 nitrogen/molecule),the nitrogen waste can be concentrated more effectivelyinasmallvolumeandtherebyhelppreservetheirtotalbody water. Smith18argued that this was critical for thesespeciestomaintainterrestriallife,especiallyunderaridconditions. However, the animal must have a cloaca thatallows the precipitation of the uric acid (present inguano)that canbeexcretedsafelywithout concernforblocking the urinary tract.Figure 1. Hypotheses for evolutionary benet of uricase mutation. The parallelmutations that occurred in early hominoid evolution in bothancestral human beings and great apes, and in lesser apes, suggests a natural selection advantage with the mutation. The primary hypothesesproposed for this mutation are shown. These include the possible role of uric acid as an extracellular antioxidant that would combat oxidativestress associated with aging, cancer, and cardiovascular disease, a role for uric acid in increasing intelligence and reaction time, and, nally,apotential roleasadangerandsurvival signal toprotectagainststarvation,butwhichintodayssocietytranslatesintoincreasedriskforobesity, diabetes, and cardiorenal disease.Uric acid and evolution 395Althoughthiscertainlyprovidesanevolutionaryad-vantage for a uricase mutation in these species, it cannotexplain why the uricase mutation occurred in humanbeings.Humanbeingscontinuetoexcretealmostalloftheir nitrogenous wastes as urea. Indeed, mammals ingeneral conservewater viaanelaborateloopof Henleconcentration mechanism. Furthermore, although themechanismfor the uricase mutationwithreptiles andbirds suggest uric acid is simply a type of waste product,theobservationthattwodifferentprimatelineagesalsolost uricasesuggeststhat uricacidalsomust havebio-logical properties.URIC ACID, INTELLIGENCE, ANDREACTIONTIMEEllis19proposedintheearly1900sthaturicacidmighthavearoleinintelligence.Henotedthatgoutwasfre-quently a disease of the educated, and that many famousphilosophers and scientists from the 1800s had gout. Thisconcept was reintroducedina letter toNature inthe1950s by Orowan,20who noted that uric acid has chem-ical characteristics similar to caffeine. Subsequently, nu-merousstudieswereperformedevaluatingtheuricacidlevelsof thegeneral populationandof special groups(university professors, students) to see if a general rela-tionship between uric acid and intelligence quotient andother intelligence tests could be identied. Most studiesshowed either weak associations or none, but the stron-gest relationship was with reaction time.21-23The possibility that uric acid may have central nervoussystem effects has not been completely ruled out. Acutehyperuricemia in rats induced by uricase inhibition doesincrease locomotor activity.24At least one studysug-gested that uric acid may increase dopamine levels in thebrain.25Indeed, hyperuricemic individuals appear to havea decreased risk for Parkinsons disease.26,27Further stud-ies are needed to assess the acute effects of hyperurice-mia on the brain.Although hyperuricemia may be associated with mildbenets on reaction time and intelligence, over time thereverseappearstobetrue. Forexample, increaseduricacidismorecommoninsubjectswithvasculardemen-tia28,29and stroke.30-32Whether this is causal has not beenshown, but it is known that experimentally hyperuricemiacaninducesmall-vessel diseaseinthekidneythat canalter autoregulation. If such events also occur in thebrain, as suggested by increased white matter disease inhyperuricemic subjects, then this would suggest that uricacid may be a cause of vascular dementia.It seems likely that the original observation by Ellis19was not owing to uric acid being associated with higherintelligence, but ratherbecausethosesubjectspronetodevelopinggout inthe1700s and1800s tendedtobewealthyandsedentary, oftenwiththeabilitytoaffordsugar, which is known to increase uric acid. Indeed,todaygout isincreasinginall populations, andifany-thingis morecommonamongthepoor andless edu-cated.33,34URIC ACIDAS ANANTIOXIDANTAmes et al35proposed in the early 1980s that the uricasemutation provided a survival advantage because uric acidcanfunctionasanantioxidant. Theseinvestigatorsandothers showedthat uricacidcouldreact withawidevariety of oxidants, especially peroxynitrite, superoxide,andhydroxyl radical.35,36Uricacidcouldbeshowntoprotect cells from oxidant injury.37Infusing uric acid intohumanbeingsalsowasshowntoacutelyincreaseanti-oxidant capacityandtoimproveendothelial cell func-tion.38-40Ames et al35suggested that the mutation in vitamin Csynthesis that had occurred 40 million years ago left earlyprimatesat increasedriskforoxidativestress. Becauseoxidativestresscoulddrivecancers,cardiovasculardis-ease, andaging, theuricasemutationthus providedasurvival advantage. In this scenario, the increase in uricacid observed in patients with cardiovascular diseaselikely was owing to a compensatory response by the hosttocombat oxidativestress.41,42Finally, theobservationthat specieswithhigheruricacidlevelstendedtolivelonger was consistent with this hypothesis.35For sure, uricacidisanantioxidant, at least intheextracellular environment. Weandothers haveshownthat uric acid potently reacts with superoxide to generateallantoin. Allantoinlevelsincreaseinhumanbeingsinresponsetooxidativestress.43-45Becausehumanbeingsdonot haveuricase, this is evidencefor adirect uricacidsuperoxide reaction. Furthermore, uric acid can re-act with peroxynitrite to form triuret.46Triuret levels areincreasedinpreeclampsiaandlikelyreect this path-way.47Uric acid also can react with nitric oxide togenerate different products, particularly 5-aminouracil.48Thus, it remains possible that the extracellular antiox-idanteffectsofuricacidcouldexplainwhytheuricasemutation resulted in a natural selection advantage. How-ever, we and others have found that uric acid is a prooxi-dant inside the cell. This has been shown in a variety ofcell types.49-51The mechanismmay be owing to theselective stimulationof nicotinamide adenine dinucle-otide phosphate oxidase.51However, uric acid also gen-erates radicals when it reacts with peroxynitrite, includ-ingthetriuret carbonyl radical andtheaminocarbonylradical.52Theintracellular prooxidativeeffects of uricacid have been shown to mediate a host of proinamma-tory effects, both in cell culture53,54and in animal mod-els.55Furthermore, recent studies have challengedwhetheruricacidreallyfunctionsasanimportantanti-oxidant in vivo.56In addition, an increased uric acid levelinhumanbeings is not associatedwithlongevity, butrather correlates withincreasedcardiovascular mortal-ity.57These ndings, coupled with increasing experimen-tal and clinical evidence for a role for uric acid in drivinghypertensionandmetabolicsyndrome, raisesquestionsastowhethertheantioxidant hypothesiscanprovideaviable mechanismfor why human beings have theuricase mutation.396 R.J. Johnson, M.A. Lanaspa, and E.A. GaucherURIC ACIDAS A MECHANISMFORAMPLIFYINGFRUCTOSEEFFECTSONFATFORMATIONAs mentioned previously the primary food staple of apesduring the mid-Miocene epoch was fruits, which are richin fructose.10Fructose is distinct fromglucose in itssuperior abilitytoincreasefat stores, includingintheliver, visceral fat, and plasma triglycerides.58,59As such,fruits were not simply a food source, but also have effectsthat can be helpful for an animal that may have intermit-tent bouts of food shortage.The specic reason why fructose is superior thanglucose in increasing fat stores likely relates to theunique rst steps in fructose metabolism. When fructoseenters the hepatocyte, it is metabolizedbya specicenzyme, fructokinase C. Unlike glucokinase, which has anegative feedback system to prevent excessive phosphor-ylation,thephosphorylationoffructosebyfructokinasewillproceeduninterrupted,andasaconsequenceintra-cellular phosphate depletion and ATP depletion fre-quently occur.60The fall in intracellular phosphate resultsinthestimulationofadenosinemonophosphate(AMP)deaminase, whichhelps accelerate the degradationofAMP to inosine monophosphate and later to uric acid.60,61In turn, the intracellular generation of uric acid results inoxidativestress.61Theseprocesseslikelyhavearoleinfattyliver formationandtriglyceride generation. Evi-dencesupportiveof thisistheconditionof hereditaryfructose intolerance, in which the subsequent enzyme infructose metabolism, aldolase B, is mutated. In this cir-cumstance, thefructosemetabolismisblocked, but thesubjects still develop fatty liver disease.62,63Inthis regard, thereis increasingevidencethat theintracellular generation of uric acid may have a role in fataccumulation. First, we have reported that uric acid caninduce proinammatory changes in the adipocyte that aresimilar to that observed in the prediabetic subject.51De-creasinguricacidalsocanreducehypertriglyceridemiaand weight gain in rats exposed to fructose.64Moreover,wehaveunpublisheddatathat uricacidregulatesboththe intestinal transporter for fructose, Glut 5, as well asthelevel of fructokinaseCintheliver. Theseeffectswould accelerate fructose absorption and, in the presenceof both increased substrate and metabolizing enzyme(fructokinase), wouldbe expectedtoresult ingreaterATPdepletionandagreater effect onfat production.Indeed, incollaborationwithDr. AbdelmalakandDr.AnnaMaeDiehl at Duke, wehavefoundthat subjectswith higher uric acid levels show greater ATP depletionin their liver in response to intravenous fructose (unpub-lished data).Giventhesecircumstances, aloss of uricasewouldpotentiatetheabilityof fructosetoincreasefat stores.Indeed, the inhibition of uricase increases the sensitivityoftherat toincreaseitsserumuricacid65anddevelopinsulin resistance to fructose.66Therefore, a mutation inuricase couldhave provideda survival advantage forMioceneapesduringtheprogressivefoodshortagethatoccurred in Europe with global cooling.10URIC ACID: A DANGERSIGNAL FROMTHE RNA WORLD?ThereisincreasingevidencethattheearliestlifeformsconsistedsolelyofRNA.67Vestigial productsfromtheRNA world that have key functions have carried over tocurrent life, such as ATP (energy) and cyclic AMP (in-tracellular messenger). It is tempting to consider thebreakdownof RNAtouricacidasapotential dangersignal for the host, and that in turn the uric acid may acttoincreasesurvival byincreasingfat stores andotherfunctions.Certainly conditions in which ATP depletion and en-ergy crisis occur are associated with an increase in uricacid.68Uric acid is released from dying cells where it hasbeen shown to activate inammation via both the innateandadaptiveimmunesystem.69-71Uricacidisanadju-vant for activation of dendritic cells69and T cells.72Uricacidalsoincreasesinthesettingofstarvationorinthelate stages of hibernation when fat stores are depleted andprotein degradation occurs.73-75In this setting it generatesa danger signal and results in a foraging response to getmorefood. Preeclampsia, aconditioninwhichthereisfetal compromise, also is associated with an increase inuricacid.76Onewondersif thehypertensionandfattyliver that occur in the mother in this condition may in partbeowingtotheincreaseinuricacid. Indeed, thereissomeevidencethat uricacidmayhaveacontributoryrole to the pathogenesis of preeclampsia.76THRIFTY GENE HYPOTHESIS ANDTHE CURRENT OBESITY EPIDEMICAn increase in uric acid may have some protective effectson survival in the setting of severe energy depletion, suchasmayoccurwithstarvation, orwithtissueinjuryandischemia. Wehypothesizethat inearlyprimatesfacedwith intermittent starvation, the loss of uricase may havetherefore provided a survival advantage.10,77An increasein uric acid may have potentiated fructose effects to gainfat, and may have led to a greater activation of theimmunesystem. Anincreaseinbloodpressureandin-creased salt sensitivity, stimulation of the renin-angioten-sinsystem, andthedevelopment of insulinresistance(whichbymaintainingincreasedbloodglucose mightpreferentially provides fuel for the brain), all would havebeenbenecial.78The abilityof uric acidtoincreasedopamine responses in the brain and to acutely stimulateincreased locomotor activity also would have been help-ful.However, what was advantageous duringstarvationmaynot bebenecial inthesettingof excessivefoodavailability. Withhigher andlessregulatableuricacidlevels we are at marked increased risk for obesity, insulinresistance, andcardiovascular andrenal diseases. WeUric acid and evolution 397havethereforeproposedthat thelossof uricaserepre-sents the thrifty gene originally proposed by Neel,79theloss of which results in a marked propensity for obesity.77REFERENCES1. Kahn K, Serfozo P, Tipton PA. Identication of the true productof the urate oxidase reaction. J Am Chem Soc. 1997;119:5435-42.2. 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