Li XY, Ji PX, Ni XX, Chen YX, Sheng L, Lian M, Guo CJ, Hua J. Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease. World J Hepatol 2022; 14(7): 1365-1381 [PMID: 36158922 DOI: 10.4254/wjh.v14.i7.1365]
Corresponding Author of This Article
Jing Hua, MD, PhD, Professor, Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), No. 160 Pujian Road, Shanghai 200127, China. hua_jing88@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 Hepatol. Jul 27, 2022; 14(7): 1365-1381 Published online Jul 27, 2022. doi: 10.4254/wjh.v14.i7.1365
Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease
Xiao-Yun Li, Pei-Xuan Ji, Xi-Xi Ni, Yu-Xin Chen, Li Sheng, Min Lian, Can-Jie Guo, Jing Hua
Xiao-Yun Li, Pei-Xuan Ji, Xi-Xi Ni, Yu-Xin Chen, Li Sheng, Min Lian, Can-Jie Guo, Jing Hua, Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
Author contributions: Li XY, Ji PX, and Ni XX contributed equally to this work; Hua J designed the research; Li XY, Ji PX and Ni XX performed the research; Chen YX, Sheng L, Lian M and Guo CJ analyzed the data; Li XY and Hua J wrote the paper.
Supported bythe National Natural Science Foundation of China, No. 81770572.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Renji Hospital.
Institutional animal care and use committee statement: All animal experiments fulfilled the Shanghai Jiao Tong University criteria for the humane treatment of laboratory animals and were approved by the Renji Hospital Animal Care and Use Committee (Permit number: RJ2018-0930). All methods were carried out in accordance with relevant guidelines and regulations.
Conflict-of-interest statement: All authors have no financial relationships to disclose.
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 noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing Hua, MD, PhD, Professor, Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), No. 160 Pujian Road, Shanghai 200127, China. hua_jing88@163.com
Received: March 26, 2022 Peer-review started: March 26, 2022 First decision: May 1, 2022 Revised: May 9, 2022 Accepted: June 22, 2022 Article in press: June 22, 2022 Published online: July 27, 2022 Processing time: 122 Days and 20.6 Hours
ARTICLE HIGHLIGHTS
Research background
Lipid metabolism disorder and inflammatory-immune activation are two vital triggers in nonalcoholic fatty liver disease (NAFLD). Little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.
Research motivation
The role of PPAR-γ in hepatocytes and in the interaction between hepatocytes and macrophages in NAFLD remain unknown.
Research objectives
To investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation and explore the potential mechanisms.
Research methods
Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocyte-specific PPAR-γ knockout mice and incubated with free fatty acids (FFAs). Macrophages were incubated with conditioned medium from lipid-laden hepatocytes with or without the PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat diet and administered rosiglitazone.
Research results
Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. Conditioned medium from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway. A PPAR-γ agonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization. Hepatocyte-specific PPAR-γ deficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes, which further promoted M1 macrophage polarization. Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.
Research conclusions
Upregulation of PPAR-γ activity alleviated NAFLD through modulation of the crosstalk between hepatocytes and macrophages via the ROS-NLRP3-IL-1β signaling pathway.
Research perspectives
To elaborate the underlying pathogenesis of NAFLD from the perspective of inflammation and immune activation.
