Huang T, Li YQX, Zhou MY, Hu RH, Zou GL, Li JC, Feng S, Liu YM, Xin CQ, Zhao XK. Focal adhesion kinase-related non-kinase ameliorates liver fibrosis by inhibiting aerobic glycolysis via the FAK/Ras/c-myc/ENO1 pathway. World J Gastroenterol 2022; 28(1): 123-139 [PMID: 35125823 DOI: 10.3748/wjg.v28.i1.123]
Corresponding Author of This Article
Xue-Ke Zhao, PhD, Professor, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang 550004, Guizhou Province, China. zhaoxueke1@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jan 7, 2022; 28(1): 123-139 Published online Jan 7, 2022. doi: 10.3748/wjg.v28.i1.123
Focal adhesion kinase-related non-kinase ameliorates liver fibrosis by inhibiting aerobic glycolysis via the FAK/Ras/c-myc/ENO1 pathway
Tao Huang, Yuan-Qing-Xiao Li, Ming-Yu Zhou, Rui-Han Hu, Gao-Liang Zou, Jian-Chao Li, Shu Feng, Yong-Mei Liu, Chang-Qin Xin, Xue-Ke Zhao
Tao Huang, Yuan-Qing-Xiao Li, Ming-Yu Zhou, Rui-Han Hu, Gao-Liang Zou, Jian-Chao Li, Shu Feng, Xue-Ke Zhao, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Yong-Mei Liu, Clinical Laboratory Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Chang-Qin Xin, Department of Infectious Diseases, People’s Hospital of Weining Yi, Hui and Miao Autonomous County, Weining 553100, Guizhou Province, China
Author contributions: Zhao XK designed the study; Huang T performed most of the experiments and wrote the article; all authors contributed to the design and interpretation of the study.
Supported bythe National Natural Science Foundation of China, No. 81860115, No. 82060116 and No. 81960118; and the Science and Technology Support Project of Guizhou Province, No. [2021] 094.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of the Affiliated Hospital of Guizhou Medical University (Approval 2018 Ethics Review No. 032).
Institutional animal care and use committee statement: Animal care and experimental procedures were authorized by the Animal Ethics Committee of Guizhou Medical University (No. 1801109).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xue-Ke Zhao, PhD, Professor, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang 550004, Guizhou Province, China. zhaoxueke1@163.com
Received: July 14, 2021 Peer-review started: July 14, 2021 First decision: October 3, 2021 Revised: October 22, 2021 Accepted: December 22, 2021 Article in press: December 22, 2021 Published online: January 7, 2022 Processing time: 170 Days and 11.5 Hours
Abstract
BACKGROUND
Hepatic stellate cell (HSC) hyperactivation is a central link in liver fibrosis development. HSCs perform aerobic glycolysis to provide energy for their activation. Focal adhesion kinase (FAK) promotes aerobic glycolysis in cancer cells or fibroblasts, while FAK-related non-kinase (FRNK) inhibits FAK phosphorylation and biological functions.
AIM
To elucidate the effect of FRNK on liver fibrosis at the level of aerobic glycolytic metabolism in HSCs.
METHODS
Mouse liver fibrosis models were established by administering CCl4, and the effect of FRNK on the degree of liver fibrosis in the model was evaluated. Transforming growth factor-β1 was used to activate LX-2 cells. Tyrosine phosphorylation at position 397 (pY397-FAK) was detected to identify activated FAK, and the expression of the glycolysis-related proteins monocarboxylate transporter 1 (MCT-1) and enolase1 (ENO1) was assessed. Bioinformatics analysis was performed to predict putative binding sites for c-myc in the ENO1 promoter region, which were validated with chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
RESULTS
The pY397-FAK level was increased in human fibrotic liver tissue. FRNK knockout promoted liver fibrosis in mouse models. It also increased the activation, migration, proliferation and aerobic glycolysis of primary hepatic stellate cells (pHSCs) but inhibited pHSC apoptosis. Nevertheless, opposite trends for these phenomena were observed after exogenous FRNK treatment in LX-2 cells. Mechanistically, the FAK/Ras/c-myc/ENO1 pathway promoted aerobic glycolysis, which was inhibited by exogenous FRNK.
CONCLUSION
FRNK inhibits aerobic glycolysis in HSCs by inhibiting the FAK/Ras/c-myc/ ENO1 pathway, thereby improving liver fibrosis. FRNK might be a potential target for liver fibrosis treatment.
Core Tip: We show that focal adhesion kinase-related non-kinase (FRNK) limits hepatic stellate cell (HSC) activation, proliferation, and migration and promotes HSC apoptosis by inhibiting aerobic glycolysis, thereby ameliorating liver fibrosis. FRNK may represent a potential therapeutic candidate for liver fibrosis treatment.
