Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver 英文参考文献.docVIP
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Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver 英文参考文献
CounteractingRolesofAMPDeaminaseandAMPKinase
intheDevelopmentofFattyLiver
MiguelA.Lanaspa1*¤,ChristinaCicerchi1,GabrielaGarcia1,NanxingLi1,CarlosA.Roncal-Jimenez1,
ChristopherJ.Rivard1,BrandiHunter1,AnaAndre′s-Hernando1,TakujiIshimoto1,LauraG.Sa′nchez-
Lozada1,JeffreyThomas1,RobertS.Hodges2,ColinT.Mant2,RichardJJohnson1
1DivisionofRenalDiseasesandHypertension,UniversityofColorado-Denver,Aurora,Colorado,UnitedStatesofAmerica,2DepartmentofBiochemistryandMolecular
Genetics,UniversityofColorado-Denver,Aurora,Colorado,UnitedStatesofAmerica
Abstract
Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine
monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and
thatitsstimulationcanpreventhepaticsteatosisbybothenhancingfatoxidationandreducinglipogenesis.Hereweshow
thatanotherAMPdependentenzyme,AMPD2,hasopposingeffectsonfattyacidoxidationwhencomparedtoAMPK.In
human hepatocytres, AMPD2 activation –either by overexpression or by lowering intracellular phosphate levels with
fructose-isassociatedwithasignificantreductioninAMPKactivity.Likewise,silencingofAMPKspontaneouslyincreases
AMPDactivity,demonstratingthattheseenzymescounter-regulateeachother.Furthermore,weshowthatadownstream
productofAMPmetabolismthroughAMPD2,uricacid,caninhibitAMPKactivityinhumanhepatocytes.Finally,weshow
that fructose-induced fat accumulation in hepatocytes is due to a dominant stimulation of AMPD2 despite stimulating
AMPK. In this regard, AMPD2-deficient hepatocytes demonstrate a further activation of AMPK after fructose exposure in
association with increased fatty acid oxidation, and conversely silencing AMPK enhances AMPD-dependent fat
accumulation.Invivo,weshowthatsucrosefedratsalsodevelopfattyliverthatisblockedbymetformininassociation
withbothareductioninAMPDactivityandanincreaseinAMPKactivity.Insummary,AMPDandAMPKarebothimportant
in hepatic fat accumulation and counter-regulat
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