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
  • 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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