Liveristhemajorsiteforcarbohydratemetabolism(glycolysisandglycogensynthesis)andtriglyceridesynthesis(lipogenesis).Whileinsulinwaslongthoughttobethemajorregulatorofhepaticgeneexpression,emergingevidenceshowthatnutrients,inparticular,glucoseandfattyacids,arealsoabletoregulatehepaticgenes.Thisdiagramillustrateshowglucosemetabolite,ratherthanglucoseitself,contributestothecoordinatedregulationofcarbohydrateandlipidhomeostasisinliverthroughphosphorylation-dependentregulationofChREBP(carbohydrateresponsiveelementbindingprotein).ChREBPisabasichelix-loophelix/leucinezipper(bHLH/LZ)transcriptionfactor,shuttlingbetweenthecytoplasmandnucleusinaglucose-responsivemannerinhepatocytes.Whenserumglucoseiselevated,glucosetransporter(GLUT2)andglucokinase(GCK)allowforrapiduptakeandequilibrationofintracellularglucoselevels.Thisfluxofglucosepromotes,viathehexosemonophosphateshuntpathway(HMPShunt),theformationofxylulose-5-phosphate(Xu-5-P),whichactivatesproteinphosphatase2A(PP2A)todephosphorylateChREBP(Ser196)andpromoteitsnuclearlocalization.PP2AfurtherdephosphorylatesChREBPinthenucleus,allowingittodimerizewiththebHLH/LZtranscriptionfactorMax-likeproteinX(MLX)andactivatetranscriptionofanumberofglycolyticandlipogenicgenescontainingaChoRE,suchasliver-typepyruvatekinase(L-PK),acetyl-CoAcarboxylase1(ACACA),andfattyacidsynthase(FASN).Uponstarvationorhigh-fatfeeding,intrahepaticlevelsofcAMPandAMPareelevatedtoactivateproteinkinaseA(PKA)andAMP-dependentproteinkinase(AMPK),respectively.PKA-mediatedphosphorylationofThr666andSer626inhibitstheDNAbindingcapacityofChREBP;sodoesAMPK-mediatedmodificationofSer568.PKA-dependentphosphorylationofSer196promotesinteractionwith14-3-3andthussequestersChREBPinthecytosol.Insummary,thephosphorylatedformofChREBPisrenderedinactiveduetoitsdiminishedDNAbindingcapacityandsubcellularcompartmentalization.GlucosemetabolismtriggersdephosphorylationofChREBP,allowingittoenterthenucleusandactivatethetranscriptionofbothglycolyticandlipogenicgeneexpressioninliver.ThefactthatChREBP–/–miceareintoleranttoglucoseandinsulinresistantsuggeststhatChREBPmayalsoplayaroleinthepathogenesisoftype2diabetes.

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