m 6 A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury

Shanshan Yu; Xiao Liu; Yan Xu; Lijie Pan; Yihan Zhang; Yanli Li; Shuai Dong; Dan Tu; Yuetong Sun; Yiwang Zhang; Zhuowei Zhou; Xiaoqi Liang; Yiju Huang; Jiajie Chu; Silin Tu; Chang Liu; Huaxin Chen; Wenjie Chen; Mian Ge; Qi Zhang

doi:10.1097/HEP.0000000000000716

m 6 A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury

Hepatology. 2023 Dec 12. doi: 10.1097/HEP.0000000000000716. Online ahead of print.

Authors

Shanshan Yu^{1

2}, Xiao Liu³, Yan Xu^{1

2

4}, Lijie Pan², Yihan Zhang³, Yanli Li¹, Shuai Dong¹, Dan Tu³, Yuetong Sun¹, Yiwang Zhang⁵, Zhuowei Zhou¹, Xiaoqi Liang², Yiju Huang², Jiajie Chu², Silin Tu¹, Chang Liu¹, Huaxin Chen¹, Wenjie Chen^{1

2

4}, Mian Ge³, Qi Zhang^{1

2

4}

Affiliations

¹ Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Cell-gene Therapy Translational Medicine Research Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Anesthesiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁵ Department of Pathology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

PMID: 38085830
DOI: 10.1097/HEP.0000000000000716

Abstract

Background and aims: Ischemia-reperfusion (I/R) injury frequently occurs during liver surgery, representing a major reason for liver failure and graft dysfunction after operation. The metabolic shift from oxidative phosphorylation to glycolysis during ischemia increased glucose consumption and accelerated lactate production. We speculate that donor livers will initiate gluconeogenesis, the reverse process of glycolysis in theory, to convert noncarbohydrate carbon substrates (including lactate) to glucose to reduce the loss of hepatocellular energy and foster glycogen storage for use in the early postoperative period, thus improving post-transplant graft function.

Approach and results: By analyzing human liver specimens before and after hepatic I/R injury, we found that the rate-limiting enzyme of gluconeogenesis, PCK1, was significantly induced during liver I/R injury. Mouse models with liver I/R operation and hepatocytes treated with hypoxia/reoxygenation confirmed upregulation of PCK1 during I/R stimulation. Notably, high PCK1 level in human post-I/R liver specimens was closely correlated with better outcomes of liver transplantation. However, blocking gluconeogenesis with PCK1 inhibitor aggravated hepatic I/R injury by decreasing glucose level and deepening lactate accumulation, while overexpressing PCK1 did the opposite. Further mechanistic study showed that methyltransferase 3-mediated RNA N6-methyladinosine modification contributes to PCK1 upregulation during hepatic I/R injury, and hepatic-specific knockout of methyltransferase 3 deteriorates liver I/R injury through reducing the N6-methyladinosine deposition on PCK1 transcript and decreasing PCK1 mRNA export and expression level.

Conclusions: Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.