PMID- 31905025
OWN - NLM
STAT- MEDLINE
DCOM- 20200511
LR  - 20200511
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Linking)
VI  - 318
IP  - 2
DP  - 2020 Feb 1
TI  - Investigating fibrosis and inflammation in an ex vivo NASH murine model.
PG  - G336-G351
LID - 10.1152/ajpgi.00209.2019 [doi]
AB  - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, 
      characterized by excess fat accumulation (steatosis). Nonalcoholic 
      steatohepatitis (NASH) develops in 15-20% of NAFLD patients and frequently 
      progresses to liver fibrosis and cirrhosis. We aimed to develop an ex vivo model 
      of inflammation and fibrosis in steatotic murine precision-cut liver slices 
      (PCLS). NASH was induced in C57Bl/6 mice on an amylin and choline-deficient 
      l-amino acid-defined (CDAA) diet. PCLS were prepared from steatohepatitic (sPCLS) 
      and control (cPCLS) livers and cultured for 48 h with LPS, TGFbeta1, or elafibranor. 
      Additionally, C57Bl/6 mice were placed on CDAA diet for 12 wk to receive 
      elafibranor or vehicle from weeks 7 to 12. Effects were assessed by transcriptome 
      analysis and procollagen Ialpha1 protein production. The diets induced features of 
      human NASH. Upon culture, all PCLS showed an increased gene expression of 
      fibrosis- and inflammation-related markers but decreased lipid metabolism 
      markers. LPS and TGFbeta1 affected sPCLS more pronouncedly than cPCLS. TGFbeta1 
      increased procollagen Ialpha1 solely in cPCLS. Elafibranor ameliorated fibrosis and 
      inflammation in vivo but not ex vivo, where it only increased the expression of 
      genes modulated by PPARalpha. sPCLS culture induced inflammation-, fibrosis-, and 
      lipid metabolism-related transcripts, explained by spontaneous activation. sPCLS 
      remained responsive to proinflammatory and profibrotic stimuli on gene 
      expression. We consider that PCLS represent a useful tool to reproducibly study 
      NASH progression. sPCLS can be used to evaluate potential treatments for NASH, as 
      demonstrated in our elafibranor study, and serves as a model to bridge results 
      from rodent studies to the human system.NEW & NOTEWORTHY This study showed that 
      nonalcoholic steatohepatitis can be studied ex vivo in precision-cut liver slices 
      obtained from murine diet-induced fatty livers. Liver slices develop a 
      spontaneous inflammatory and fibrogenic response during culture that can be 
      augmented with specific modulators. Additionally, the model can be used to test 
      the efficacy of pharmaceutical compounds (as shown in this investigation with 
      elafibranor) and could be a tool for preclinical assessment of potential 
      therapies.
FAU - Gore, Emilia
AU  - Gore E
AD  - Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, 
      The Netherlands.
FAU - Bigaeva, Emilia
AU  - Bigaeva E
AD  - Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, 
      The Netherlands.
FAU - Oldenburger, Anouk
AU  - Oldenburger A
AD  - CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach an der 
      Riss, Germany.
FAU - Jansen, Yvette J M
AU  - Jansen YJM
AD  - Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, 
      The Netherlands.
FAU - Schuppan, Detlef
AU  - Schuppan D
AD  - Institute of Translational Immunology and Research Center for Immunotherapy, 
      University Medical Center, Johannes Gutenberg University, Mainz, Germany.
AD  - Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard 
      Medical School, Boston, Massachusetts.
FAU - Boersema, Miriam
AU  - Boersema M
AD  - Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, 
      The Netherlands.
FAU - Rippmann, Jorg F
AU  - Rippmann JF
AD  - CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach an der 
      Riss, Germany.
FAU - Broermann, Andre
AU  - Broermann A
AD  - CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach an der 
      Riss, Germany.
FAU - Olinga, Peter
AU  - Olinga P
AD  - Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, 
      The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200106
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 
      (2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic 
      acid)
RN  - 0 (Chalcones)
RN  - 0 (Collagen Type I)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Propionates)
RN  - 0 (Transforming Growth Factor beta1)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chalcones/pharmacology
MH  - Collagen Type I/biosynthesis
MH  - Diet
MH  - Disease Models, Animal
MH  - In Vitro Techniques
MH  - Inflammation/*pathology
MH  - Lipid Metabolism/genetics
MH  - Lipopolysaccharides/pharmacology
MH  - Liver/pathology
MH  - Liver Cirrhosis/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Non-alcoholic Fatty Liver Disease/*pathology
MH  - Propionates/pharmacology
MH  - Transcriptome/genetics
MH  - Transforming Growth Factor beta1/pharmacology
OTO - NOTNLM
OT  - elafibranor
OT  - fibrosis
OT  - inflammation
OT  - nonalcoholic steatohepatitis
OT  - precision-cut liver slices
EDAT- 2020/01/07 06:00
MHDA- 2020/05/12 06:00
CRDT- 2020/01/07 06:00
PHST- 2020/01/07 06:00 [pubmed]
PHST- 2020/05/12 06:00 [medline]
PHST- 2020/01/07 06:00 [entrez]
AID - 10.1152/ajpgi.00209.2019 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2020 Feb 1;318(2):G336-G351. doi: 
      10.1152/ajpgi.00209.2019. Epub 2020 Jan 6.