Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
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 by the 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
Abstract
BACKGROUND

Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Various studies have shown that PPAR-γ exerts potent anti-inflammatory and immunomodulatory properties. However, little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.

AIM

To investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation.

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 (CM) from lipid-laden hepatocytes with or without a PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat (HF) diet and administered rosiglitazone.

RESULTS

Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. CM 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.

CONCLUSION

Upregulation of PPAR-γ activity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β pathway.

Keywords: Nonalcoholic fatty liver disease, Hepatocyte, Macrophage polarization, PPAR-γ, NLRP3, Oxidative stress

Core Tip: Nonalcoholic fatty liver disease (NAFLD) is currently one of the most endemic chronic liver diseases worldwide. We aimed to investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and to explore the underlying mechanism. Our study revealed that lipid-laden hepatocytes skewed macrophage polarization to the M1 phenotype. Regulation of PPAR-γ activity alleviates NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β signaling pathway. Strategies that manipulate PPAR-γ activity to regulate cell crosstalk will be beneficial for treating NAFLD.