Published online Jul 27, 2022. doi: 10.4254/wjh.v14.i7.1365
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
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.
The role of PPAR-γ in hepatocytes and in the interaction between hepatocytes and macrophages in NAFLD remain unknown.
To investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation and explore the potential mechanisms.
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.
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.
Upregulation of PPAR-γ activity alleviated NAFLD through modulation of the crosstalk between hepatocytes and macrophages via the ROS-NLRP3-IL-1β signaling pathway.
To elaborate the underlying pathogenesis of NAFLD from the perspective of inflammation and immune activation.