Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury

Qiang Zhao; Xiaobo Wang; Kunpeng Liu; Honghui Chen; Jia Dan; Zebin Zhu; Lili Guo; Huadi Chen; Weiqiang Ju; Dongping Wang; Yunhua Tang; Zhiyong Guo; Xiaoshun He

doi:10.1016/j.ajt.2024.04.003

Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury

Am J Transplant. 2024 Apr 12:S1600-6135(24)00274-0. doi: 10.1016/j.ajt.2024.04.003. Online ahead of print.

Authors

Qiang Zhao¹, Xiaobo Wang¹, Kunpeng Liu², Honghui Chen¹, Jia Dan¹, Zebin Zhu³, Lili Guo¹, Huadi Chen¹, Weiqiang Ju¹, Dongping Wang¹, Yunhua Tang⁴, Zhiyong Guo⁵, Xiaoshun He⁶

Affiliations

¹ Organ Transplant Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Liver Disease, Cell-Gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
³ Organ Transplant Center, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
⁴ Organ Transplant Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China. Electronic address: tang_yunhua@163.com.
⁵ Organ Transplant Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China. Electronic address: rockyucsf1981@126.com.
⁶ Organ Transplant Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China. Electronic address: gdtrc@163.com.

PMID: 38615902
DOI: 10.1016/j.ajt.2024.04.003

Abstract

The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.

Keywords: NF-κB; farnesoid X receptor; ischemia-reperfusion injury; liver transplantation; normothermic machine perfusion.