PMID- 32890136
OWN - NLM
STAT- MEDLINE
DCOM- 20210720
LR  - 20231002
IS  - 1534-6080 (Electronic)
IS  - 0041-1337 (Linking)
VI  - 105
IP  - 3
DP  - 2021 Mar 1
TI  - Inhibition of Carnitine Palmitoyltransferase 1A Aggravates Fatty Liver Graft 
      Injury via Promoting Mitochondrial Permeability Transition.
PG  - 550-560
LID - 10.1097/TP.0000000000003437 [doi]
AB  - BACKGROUND: 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.
CI  - Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Xue, Yan
AU  - Xue Y
AD  - Department of Surgery, HKU-SZH &LKS Faculty of Medicine, The University of Hong 
      Kong, Pokfulam, Hong Kong, China.
FAU - Liu, Hui
AU  - Liu H
FAU - Yang, Xin-Xiang
AU  - Yang XX
FAU - Pang, Li
AU  - Pang L
FAU - Liu, Jiang
AU  - Liu J
FAU - Ng, Kevin T P
AU  - Ng KTP
FAU - Yeung, Oscar W H
AU  - Yeung OWH
FAU - Lam, Yin-Fan
AU  - Lam YF
FAU - Zhang, Wei-Yi
AU  - Zhang WY
FAU - Lo, Chung-Mau
AU  - Lo CM
FAU - Man, Kwan
AU  - Man K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/antagonists & inhibitors/*metabolism
MH  - Cell Line
MH  - Disease Models, Animal
MH  - Fatty Liver/*drug therapy/etiology/metabolism
MH  - Female
MH  - Humans
MH  - Liver/*metabolism/pathology
MH  - Liver Transplantation/*adverse effects
MH  - Male
MH  - Mice
MH  - Mitochondrial Transmembrane Permeability-Driven Necrosis
MH  - Reperfusion Injury/*drug therapy/metabolism/pathology
MH  - Retrospective Studies
COIS- The authors declare no conflicts of interest.
EDAT- 2020/09/06 06:00
MHDA- 2021/07/21 06:00
CRDT- 2020/09/05 17:06
PHST- 2020/09/06 06:00 [pubmed]
PHST- 2021/07/21 06:00 [medline]
PHST- 2020/09/05 17:06 [entrez]
AID - 00007890-202103000-00017 [pii]
AID - 10.1097/TP.0000000000003437 [doi]
PST - ppublish
SO  - Transplantation. 2021 Mar 1;105(3):550-560. doi: 10.1097/TP.0000000000003437.