Integrative Network Analysis Revealed Genetic Impact of Pyruvate Kinase L/R on Hepatocyte Proliferation and Graft Survival after Liver Transplantation.

Zhengtao Liu,Shusen Zheng,Shuai Wang,Feng Zhang,Shengyong Yin,Hai Zhu,Junsheng Zhao,Shuping Que,Lin Zhou,Lei Geng,Junjie Qian,Wenchao Wang,Xianquan Zhan

doi:10.1155/2021/7182914

Abstract

Background Pyruvate kinase L/R (PKLR) has been suggested to affect the proliferation of hepatocytes via regulation of the cell cycle and lipid metabolism. However, its impact on the global metabolome and its clinical implications remain unclear. Aims We aimed to clarify the genetic impact of PKLR on the metabolomic profiles of hepatoma cells and its potential effects on grafts for liver transplantation (LT). Methods Nontargeted and targeted metabolomic assays were performed in human hepatoma cells transfected with lentiviral vectors causing PKLR overexpression and silencing, respectively. We then constructed a molecular network based on integrative analysis of transcriptomic and metabolomic data. We also assessed the biological functions of PKLR in the global metabolome in LT grafts in patients via a weighted correlation network model. Results Multiomic analysis revealed that PKLR perturbations significantly affected the pyruvate, citrate, and glycerophospholipid metabolism pathways, as crucial steps in de novo lipogenesis (DNL). We also confirmed the importance of phosphatidylcholines (PC) and its derivative lyso-PC supply on improved survival of LT grafts in patients. Coexpression analysis revealed beneficial effects of PKLR overexpression on posttransplant prognosis by alleviating arachidonic acid metabolism of the grafts, independent of operational risk factors. Conclusion This systems-level analysis indicated that PKLR affected hepatoma cell viability via impacts on the whole process of DNL, from glycolysis to final PC synthesis. PKLR also improved prognosis after LT, possibly via its impact on the increased genesis of beneficial glycerophospholipids.

Highlights

The liver acts as the central hub organ for the complex energy metabolism networks in human bodies [1]
Compared with NC samples, transfection with open reading frame particles resulted in an increase of PKLP of about 4.7-fold, while transfection with short hairpin RNA (shRNA) caused an approximately 70% decrease in Pyruvate kinase L/R (PKLR) mRNA expression
We previously found that PKLR was coexpressed with Fatty Acid Synthase (FASN) as the key gene of de novo lipogenesis (DNL) in the liver [7], and the current integrative multiomic analysis confirmed that PKLR per se was involved in DNL

Summary

Introduction

The liver acts as the central hub organ for the complex energy metabolism networks in human bodies [1]. Transcriptomic data further revealed that PKLR might affect cell viability via regulating liver mitochondrial function [8]. Pyruvate kinase L/R (PKLR) has been suggested to affect the proliferation of hepatocytes via regulation of the cell cycle and lipid metabolism. We aimed to clarify the genetic impact of PKLR on the metabolomic profiles of hepatoma cells and its potential effects on grafts for liver transplantation (LT). Multiomic analysis revealed that PKLR perturbations significantly affected the pyruvate, citrate, and glycerophospholipid metabolism pathways, as crucial steps in de novo lipogenesis (DNL). Coexpression analysis revealed beneficial effects of PKLR overexpression on posttransplant prognosis by alleviating arachidonic acid metabolism of the grafts, independent of operational risk factors. This systems-level analysis indicated that PKLR affected hepatoma cell viability via impacts on the whole process of DNL, from glycolysis to final PC synthesis. PKLR improved prognosis after LT, possibly via its impact on the increased genesis of beneficial glycerophospholipids

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Results

Discussion

Conclusion