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Article: Inhibition of carnitine palmitoyltransferase 1A aggravates fatty liver graft injury via promoting mitochondrial permeability transition

TitleInhibition of carnitine palmitoyltransferase 1A aggravates fatty liver graft injury via promoting mitochondrial permeability transition
Authors
Issue Date2021
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.transplantjournal.com
Citation
Transplantation, 2021, v. 105 n. 3, p. 550-560 How to Cite?
AbstractBackground. Hepatic steatosis is a major risk factor for graft failure due to increased susceptibility of fatty liver to ischemia-reperfusion injury (IRI) during transplantation. Here, we aimed to investigate the role of carnitine palmitoyltransferase 1A (CPT1A) in fatty liver graft injury and to explore the underlying mechanism and therapeutic potential on attenuating hepatic IRI. Methods. Intragraft CPT1A expression profile and the association with fatty graft injury were investigated in human and rat liver transplantation samples. The underlying mechanism and therapeutic potential of CPT1A activator against IRI were also explored in mouse hepatic ischemia-reperfusion plus major hepatectomy model and in in vitro. Results. CPT1A expression was significantly reduced (P = 0.0019; n = 96) in human fatty liver graft compared with normal one at early phase after transplantation. Low expression of CPT1A was significantly associated with high serum alanine aminotransferase (P = 0.0144) and aspartate aminotransferase (P = 0.0060) levels. The inhibited CPT1A and poor liver function were consistently observed in rat and mouse models with fatty livers. Furthermore, inhibition of CPT1A significantly promoted the translocation of chloride intracellular channel 1 to form chloride ion channel. The dysregulation of chloride ion channel activity subsequently triggered mitochondrial permeability transition (MPT) pore opening, exacerbated cellular oxidative stress, and energy depletion. Importantly, our intravital confocal imaging showed that CPT1A activation attenuated hepatic injury through preventing MPT after reperfusion in fatty mice. Conclusions. CPT1A inhibition triggered MPT contributed to severe IRI in fatty liver graft. CPT1A restoration may offer therapeutic potential on attenuating hepatic IRI.
Persistent Identifierhttp://hdl.handle.net/10722/288184
ISSN
2023 Impact Factor: 5.3
2023 SCImago Journal Rankings: 1.371
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorXue, Y-
dc.contributor.authorLiu, H-
dc.contributor.authorYang, XX-
dc.contributor.authorLi, P-
dc.contributor.authorLiu, J-
dc.contributor.authorNg, KTP-
dc.contributor.authorYeung, O-
dc.contributor.authorLam, YF-
dc.contributor.authorZhang, WY-
dc.contributor.authorLo, CM-
dc.contributor.authorMan, K-
dc.date.accessioned2020-10-05T12:09:06Z-
dc.date.available2020-10-05T12:09:06Z-
dc.date.issued2021-
dc.identifier.citationTransplantation, 2021, v. 105 n. 3, p. 550-560-
dc.identifier.issn0041-1337-
dc.identifier.urihttp://hdl.handle.net/10722/288184-
dc.description.abstractBackground. Hepatic steatosis is a major risk factor for graft failure due to increased susceptibility of fatty liver to ischemia-reperfusion injury (IRI) during transplantation. Here, we aimed to investigate the role of carnitine palmitoyltransferase 1A (CPT1A) in fatty liver graft injury and to explore the underlying mechanism and therapeutic potential on attenuating hepatic IRI. Methods. Intragraft CPT1A expression profile and the association with fatty graft injury were investigated in human and rat liver transplantation samples. The underlying mechanism and therapeutic potential of CPT1A activator against IRI were also explored in mouse hepatic ischemia-reperfusion plus major hepatectomy model and in in vitro. Results. CPT1A expression was significantly reduced (P = 0.0019; n = 96) in human fatty liver graft compared with normal one at early phase after transplantation. Low expression of CPT1A was significantly associated with high serum alanine aminotransferase (P = 0.0144) and aspartate aminotransferase (P = 0.0060) levels. The inhibited CPT1A and poor liver function were consistently observed in rat and mouse models with fatty livers. Furthermore, inhibition of CPT1A significantly promoted the translocation of chloride intracellular channel 1 to form chloride ion channel. The dysregulation of chloride ion channel activity subsequently triggered mitochondrial permeability transition (MPT) pore opening, exacerbated cellular oxidative stress, and energy depletion. Importantly, our intravital confocal imaging showed that CPT1A activation attenuated hepatic injury through preventing MPT after reperfusion in fatty mice. Conclusions. CPT1A inhibition triggered MPT contributed to severe IRI in fatty liver graft. CPT1A restoration may offer therapeutic potential on attenuating hepatic IRI.-
dc.languageeng-
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.transplantjournal.com-
dc.relation.ispartofTransplantation-
dc.rightsThis is a non-final version of an article published in final form in (provide complete journal citation)-
dc.titleInhibition of carnitine palmitoyltransferase 1A aggravates fatty liver graft injury via promoting mitochondrial permeability transition-
dc.typeArticle-
dc.identifier.emailXue, Y: yan2016@HKUCC-COM.hku.hk-
dc.identifier.emailLiu, H: liuhui25@hku.hk-
dc.identifier.emailNg, KTP: ledodes@hku.hk-
dc.identifier.emailYeung, O: why21@hku.hk-
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.authorityNg, KTP=rp01720-
dc.identifier.authorityLo, CM=rp00412-
dc.identifier.authorityMan, K=rp00417-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1097/TP.0000000000003437-
dc.identifier.pmid32890136-
dc.identifier.scopuseid_2-s2.0-85102221625-
dc.identifier.hkuros315031-
dc.identifier.volume105-
dc.identifier.issue3-
dc.identifier.spage550-
dc.identifier.epage560-
dc.identifier.isiWOS:000639592700024-
dc.publisher.placeUnited States-
dc.identifier.issnl0041-1337-

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