PMID- 36165186
OWN - NLM
STAT- MEDLINE
DCOM- 20221124
LR  - 20221216
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 42
IP  - 12
DP  - 2022 Dec
TI  - Regulation of the macrophage-hepatic stellate cell interaction by targeting 
      macrophage peroxisome proliferator-activated receptor gamma to prevent 
      non-alcoholic steatohepatitis progression in mice.
PG  - 2696-2712
LID - 10.1111/liv.15441 [doi]
AB  - BACKGROUND & AIMS: Macrophages display remarkable plasticity and can interact 
      with surrounding cells to affect hepatic immunity and tissue remodelling during 
      the progression of liver diseases. Peroxisome proliferator-activated receptor 
      gamma (PPARgamma) plays a critical role in macrophage maturation, polarization and 
      metabolism. In this study, we investigated the role of PPARgamma in 
      macrophage-hepatic stellate cell (HSC) interaction during non-alcoholic 
      steatohepatitis (NASH) development. METHODS: Wild-type, Pparg(fl/fl) and 
      Pparg(DeltaLyz2) mice were fed a methionine- and choline-deficient (MCD) diet to 
      induce NASH. Depletion of macrophages was performed using an injection of 
      gadolinium chloride intraperitoneally. PPARgamma-overexpressing or PPARgamma-knockout 
      macrophages were stimulated with saturated fatty acid (SFA) and cocultured with 
      HSCs in a conditioned medium or the transwell coculture system. RESULTS: 
      Depletion of macrophages inhibited HSC activation and ameliorated NASH 
      progression in MCD diet-fed mice. Coculturing HSCs with macrophages or culturing 
      HSCs in a macrophage-conditioned medium-facilitated HSC activation, and this 
      effect was magnified when macrophages were metabolically activated by SFA. 
      Moreover, the absence of PPARgamma in macrophages enhanced metabolic activation, 
      promoting the migration and activation of HSCs through IL-1beta and CCL2. In 
      contrast, overexpression of PPARgamma in macrophages obtained the opposite effects. 
      In vivo, macrophage-specific PPARgamma knockout affected the phenotype of hepatic 
      macrophages and HSCs, involving the MAPK and NLRP3/caspase-1/IL-1beta signalling 
      pathways. Infiltrating hepatic monocyte-derived macrophages became the 
      predominant macrophages in NASH liver, especially in Pparg(DeltaLyz2) mice, 
      paralleling with aggravated inflammation and fibrosis. CONCLUSIONS: Regulating 
      macrophage PPARgamma affected the metabolic activation of macrophages and their 
      interaction with HSCs. Macrophage-specific PPARgamma may be an attractive therapeutic 
      target for protecting against NASH-associated inflammation and fibrosis.
CI  - (c) 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Ni, Xi Xi
AU  - Ni XX
AUID- ORCID: 0000-0003-3361-3703
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Ji, Pei Xuan
AU  - Ji PX
AUID- ORCID: 0000-0002-6905-9647
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Chen, Yu Xin
AU  - Chen YX
AUID- ORCID: 0000-0002-0359-5674
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Li, Xiao Yun
AU  - Li XY
AUID- ORCID: 0000-0003-4706-6114
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Sheng, Li
AU  - Sheng L
AUID- ORCID: 0000-0002-3641-5211
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Lian, Min
AU  - Lian M
AUID- ORCID: 0000-0003-2122-1614
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Guo, Can Jie
AU  - Guo CJ
AUID- ORCID: 0000-0001-5951-299X
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Hua, Jing
AU  - Hua J
AUID- ORCID: 0000-0002-6100-9477
AD  - Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive 
      Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of 
      Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221011
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (PPAR gamma)
RN  - 0 (Culture Media, Conditioned)
RN  - AE28F7PNPL (Methionine)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Hepatic Stellate Cells/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/prevention & control/metabolism
MH  - PPAR gamma/metabolism
MH  - Culture Media, Conditioned/metabolism
MH  - Mice, Inbred C57BL
MH  - Macrophages/metabolism
MH  - Liver/metabolism
MH  - Liver Cirrhosis/pathology
MH  - Inflammation/pathology
MH  - Methionine/metabolism
OTO - NOTNLM
OT  - PPAR gamma
OT  - fibrosis
OT  - hepatic stellate cells
OT  - inflammation
OT  - macrophages
OT  - non-alcoholic fatty liver disease
EDAT- 2022/09/28 06:00
MHDA- 2022/11/25 06:00
CRDT- 2022/09/27 06:13
PHST- 2022/09/22 00:00 [revised]
PHST- 2022/05/10 00:00 [received]
PHST- 2022/09/23 00:00 [accepted]
PHST- 2022/09/28 06:00 [pubmed]
PHST- 2022/11/25 06:00 [medline]
PHST- 2022/09/27 06:13 [entrez]
AID - 10.1111/liv.15441 [doi]
PST - ppublish
SO  - Liver Int. 2022 Dec;42(12):2696-2712. doi: 10.1111/liv.15441. Epub 2022 Oct 11.