Abstract
The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS.
Highlights
Misfolded or damaged proteins are degraded by cells without the non-specific destruction of essential cell constituents [1]
The present study focuses on the relevance of the ubiquitin proteasome system (UPS) dysregulation associated with liver ischemic injury which occurs when fatty liver grafts are preserved in HTK or IGL-1 solutions, and aims to identify and discuss a variety of protective preservation mechanisms
We found a significant activation of adenosine monophosphate protein kinase (AMPK) in fatty livers preserved in IGL-1 solution but not in those preserved in HTK solution
Summary
Misfolded or damaged proteins are degraded by cells without the non-specific destruction of essential cell constituents [1]. The 26S proteasome is composed of a core 20S particle, in which proteins are digested to short peptides, and one or two 19S regulatory particles that are responsible for substrate recognition and transport into the core particle [3] These particles are known to participate in degradation and folding of many regulatory proteins that are involved in cell cycle, metabolism, inflammation and growth, and in other processes including ischemia-reperfusion injury (IRI) [4,5]. HHiissttoolologgyyhheemmaatotoxxyylilnin––eoeosisninstsatianiinnign.gP.(ChPo)htoomtoimcriocrgorgaprahpshosf olifvleirvsearts 2a0t×2m0×agmniafgicnaitfiiocna:ti(oAn): (CFAiog)nutCrroeoln2t.rgHorloisugtoprloousgphyohswheimonwgationnxgoyrlnimno–armel oashlienphsaettpaiicantiancrgca.hrPcitheoicttteoucmrtueircerwowgitrhiathpmhmsaocarfcorli-ov-earansndadt 2mm0i×iccrmroo-a-vvgenessiificicucuallatairor nff:aa(ttAttyy) iiCnnoffiinlltttrrraaottliioongn;r;o((BuBp)) HHsTThKoKwggirnrooguuppn..oErExmtxetanelsnisvhieevpeaarateiracesaasorfocchfeictlel lcdltiudsrsiesoscoiwactiiatohtnio,mnc,ealcclerslolw-sewallneindllginmagniadcrnodd-ivsdienisstiiecngutrleaagrtrioafntaiototnyf hoinfefphilaettrpiacattiaoicrnca;hr(icBthe)citHteucTrteKuragerreaorusepese.enEexn(tCe(Cn) s)IiGvIGeLLagrgeroraousupop.f.WcW elelelldl-lp-isprseroescesieravrtveioednd,lolcobeblululsalawrreaalrlrcicnhhgiitteaecncttduurrdeeiswwiniitthehgmrmaitinnioiimnmaaollf sshiiennpuuasstooiiicddaallrcddhiilliaatettaacttuiioornne aaannrdde ccseeellellnssww(eCelll)liinnIgGg Laarreegoroobbusseperr.vvWeedde..ll-preserved lobular architecture with minimal sinusoidal dilatation and cell swelling are observed These results were consistent with the higher prevention of mitochondrial damage, determined by GTLhDeHsearcetsivuiltys wleevreelsc,oinsliisvternst pwrietshetrhvedhiignhIeGrLp-r1evsoenlutitoionnotfhmanitionchliovnedrsriparledsaemrvaegde,indeHteTrKm. iTnehde hbyistGolLoDgiHc satuctdiyviotyf cloevnetrlos,l sintealitvoetircs lpivreerssersvheodweind IgGraLd-1e IsIotloutIiIoI noftfhaatntyiinnfliilvtreartsiopnr,ewseirthvehdepinatoHcTyKte. Tinhteghriisttyolmogaicinstteundaynocef .coTnhterool tshteeartogtrioculipvsercsosnhsoewrveeddgrfatdteyIiIntfoilItIrIaotifofnat.tyThinefimltroastitosne,vweirteh chheapnagtoecsyitne hinistetoglroitgyymwaeirneteonbasnercve.edThine tohteheHrTgKrogurposucpo, nssheorwveindgfastetvyerineficletlrlautliaornd.
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