2. Academic Validation
  3. Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin-Mediated Mitophagy

Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin-Mediated Mitophagy

  • Cell Mol Gastroenterol Hepatol. 2024;17(1):149-169. doi: 10.1016/j.jcmgh.2023.09.004.
Yu Zhang 1,  Ziyi Wang 1,  Chenyang Jia 2,  Wenjie Yu 1,  Xiangdong Li 1,  Nan Xia 1,  Huiling Nie 3,  Likalamu Pascalia Wikana 1,  Minhao Chen 1,  Yong Ni 4,  Sheng Han 5,  Liyong Pu 6
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China.
  • 2 Department of Hepatopancreatobiliary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
  • 3 Affiliated Eye Hospital and Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 4 Department of Hepatopancreatobiliary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China. Electronic address: [email protected].
  • 5 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].
  • 6 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].
PMID: 37717824 DOI: 10.1016/j.jcmgh.2023.09.004
Abstract

Background & aims: Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury.

Methods: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response.

Results: Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on Mitophagy.

Conclusions: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by Reactive Oxygen Species and mitochondrial DNA by promoting PINK1-Parkin-mediated Mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.

Keywords

Hepatic Ischemia-Reperfusion; Mitophagy; PCSK9; PINK1; STING.

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