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

Yu Zhang; Ziyi Wang; Chenyang Jia; Wenjie Yu; Xiangdong Li; Nan Xia; Huiling Nie; Likalamu Pascalia Wikana; Minhao Chen; Yong Ni; Sheng Han; Liyong Pu

Cellular and Molecular Gastroenterology and Hepatology (Jan 2024)

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

Yu Zhang,
Ziyi Wang,
Chenyang Jia,
Wenjie Yu,
Xiangdong Li,
Nan Xia,
Huiling Nie,
Likalamu Pascalia Wikana,
Minhao Chen,
Yong Ni,
Sheng Han,
Liyong Pu

Affiliations

Yu Zhang: 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
Ziyi Wang: 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
Chenyang Jia: Department of Hepatopancreatobiliary Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Wenjie Yu: 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
Xiangdong Li: 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
Nan Xia: 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
Huiling Nie: Affiliated Eye Hospital and Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
Likalamu Pascalia Wikana: 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
Minhao Chen: 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
Yong Ni: Department of Hepatopancreatobiliary Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China; Yong Ni, MD, PhD, Department of Hepatopancreatobiliary Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, China
Sheng Han: 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; Sheng Han, PhD, Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiang Su province 210003, China.
Liyong Pu: 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; Correspondence Address correspondence to: Liyona Pu, PhD, MD, Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiang Su province 210003, China.

Journal volume & issue: Vol. 17, no. 1
pp. 149 – 169

Abstract

Read online

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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

About the journal

Abstract

Keywords