PMID- 23831119
OWN - NLM
STAT- MEDLINE
DCOM- 20140930
LR  - 20210103
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 59
IP  - 5
DP  - 2013 Nov
TI  - Cell-specific PPARgamma deficiency establishes anti-inflammatory and anti-fibrogenic 
      properties for this nuclear receptor in non-parenchymal liver cells.
PG  - 1045-53
LID - S0168-8278(13)00440-6 [pii]
LID - 10.1016/j.jhep.2013.06.023 [doi]
AB  - BACKGROUND & AIMS: PPARgamma plays an essential role in the transcriptional 
      regulation of genes involved in lipid and glucose metabolism, insulin 
      sensitivity, and inflammation. We recently demonstrated that PPARgamma plays a 
      causative role in hepatocyte lipid deposition, contributing to the pathogenesis 
      of hepatic steatosis. In this study, we investigated the role of PPARgamma in the 
      inflammatory and fibrogenic response of the liver. METHODS: Heterozygous 
      floxed/null Cre/LoxP mice with targeted deletion of PPARgamma in either hepatocytes 
      (Alb-Cre), macrophages (LysM-Cre) or hepatic stellate cells (HSCs) (aP2-Cre) were 
      submitted to carbon tetrachloride (CCl4) liver injury. Further analyses were 
      performed in precision-cut liver slices (PCLS) and primary cultures of 
      hepatocytes, macrophages, and HSCs. RESULTS: LysM-Cre mice displayed an 
      exacerbated response to chronic CCl4 injury and showed higher necroinflammatory 
      injury, lipid peroxidation, inflammatory infiltrate, cleaved-caspase-3 and 
      caspase 3/7 activity, and COX-2, TNF-alpha, CXCL2, and IL-1beta expression than Alb-Cre 
      and control mice. The deleterious effects of PPARgamma disruption in liver 
      macrophages were confirmed in an acute model of CCl4 injury as well as in PCLS 
      incubated with LPS. Moreover, LysM-Cre mice showed an aggravated fibrogenic 
      response to CCl4, as revealed by more prominent Sirius Red and Masson's trichrome 
      staining, elevated hydroxyproline content and induced alpha-SMA and TIMP-1 
      expression. Importantly, aP2-Cre mice with specific disruption of PPARgamma in HSCs, 
      as confirmed by immunocytochemical analysis of individual liver cells, also 
      showed exacerbated liver damage and fibrogenic response to CCl4. CONCLUSIONS: 
      These data unveil anti-inflammatory and anti-fibrogenic roles for PPARgamma in 
      non-parenchymal liver cells.
CI  - Copyright (c) 2013 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Moran-Salvador, Eva
AU  - Moran-Salvador E
AD  - Department of Biochemistry and Molecular Genetics, Hospital Clinic-IDIBAPS-Esther 
      Koplowitz Center, Barcelona, Spain.
FAU - Titos, Esther
AU  - Titos E
FAU - Rius, Bibiana
AU  - Rius B
FAU - Gonzalez-Periz, Ana
AU  - Gonzalez-Periz A
FAU - Garcia-Alonso, Veronica
AU  - Garcia-Alonso V
FAU - Lopez-Vicario, Cristina
AU  - Lopez-Vicario C
FAU - Miquel, Rosa
AU  - Miquel R
FAU - Barak, Yaacov
AU  - Barak Y
FAU - Arroyo, Vicente
AU  - Arroyo V
FAU - Claria, Joan
AU  - Claria J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130702
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Actins)
RN  - 0 (PPAR gamma)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
SB  - IM
CIN - J Hepatol. 2013 Nov;59(5):915-7. PMID: 23958934
MH  - Actins/metabolism
MH  - Animals
MH  - Carbon Tetrachloride/adverse effects
MH  - Cells, Cultured
MH  - Chemical and Drug Induced Liver Injury/metabolism/pathology/physiopathology
MH  - Disease Models, Animal
MH  - Hepatic Stellate Cells/metabolism/*pathology
MH  - Hepatocytes/metabolism/*pathology
MH  - Inflammation/*physiopathology
MH  - Liver Cirrhosis/*physiopathology
MH  - Macrophages/metabolism/*pathology
MH  - Mice
MH  - Mice, Knockout
MH  - PPAR gamma/*deficiency/genetics/*physiology
MH  - Receptors, Cytoplasmic and Nuclear/deficiency/genetics/physiology
MH  - Tissue Inhibitor of Metalloproteinase-1/metabolism
OTO - NOTNLM
OT  - 4-HNE
OT  - 4-hydroxynonenal
OT  - ALT
OT  - AST
OT  - Alb-Cre
OT  - CCl(4)
OT  - Fibrosis
OT  - HSCs
OT  - Hepatic stellate cells
OT  - Hepatocytes
OT  - IL
OT  - Inflammation
OT  - Kupffer cells
OT  - LDH
OT  - LPS
OT  - LysM-Cre
OT  - NAFLD
OT  - NF-kappaB
OT  - PCLS
OT  - PPARgamma
OT  - TNF-alpha
OT  - TZD
OT  - aP2-Cre
OT  - adipocyte fatty acid-binding protein 4-Cre (HSC-specific PPARgamma deficient mice)
OT  - alanine aminotransferase
OT  - albumin-Cre (hepatocyte-specific PPARgamma deficient mice)
OT  - aspartate aminotransferase
OT  - carbon tetrachloride
OT  - hepatic stellate cells
OT  - interleukin
OT  - lactate dehydrogenase
OT  - lipopolysaccharide
OT  - lysozyme M-Cre (macrophage-specific PPARgamma deficient mice)
OT  - non-alcoholic fatty liver disease
OT  - nuclear factor-kB
OT  - peroxisome proliferator-activated receptor gamma
OT  - precision-cut liver slices
OT  - thiazolidinediones
OT  - tumor necrosis factor alpha
EDAT- 2013/07/09 06:00
MHDA- 2014/10/01 06:00
CRDT- 2013/07/09 06:00
PHST- 2013/03/06 00:00 [received]
PHST- 2013/06/19 00:00 [revised]
PHST- 2013/06/24 00:00 [accepted]
PHST- 2013/07/09 06:00 [entrez]
PHST- 2013/07/09 06:00 [pubmed]
PHST- 2014/10/01 06:00 [medline]
AID - S0168-8278(13)00440-6 [pii]
AID - 10.1016/j.jhep.2013.06.023 [doi]
PST - ppublish
SO  - J Hepatol. 2013 Nov;59(5):1045-53. doi: 10.1016/j.jhep.2013.06.023. Epub 2013 Jul 
      2.