PMID- 24489787
OWN - NLM
STAT- MEDLINE
DCOM- 20140929
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter 
      lipid metabolism by different mechanisms in mouse liver slices.
PG  - e86795
LID - 10.1371/journal.pone.0086795 [doi]
LID - e86795
AB  - Although drug induced steatosis represents a mild type of hepatotoxicity it can 
      progress into more severe non-alcoholic steatohepatitis. Current models used for 
      safety assessment in drug development and chemical risk assessment do not 
      accurately predict steatosis in humans. Therefore, new models need to be 
      developed to screen compounds for steatogenic properties. We have studied the 
      usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal 
      testing to gain more insight into the mechanisms involved in the steatogenesis. 
      To this end, PCLS were incubated 24 h with the model steatogenic compounds: 
      amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome 
      analysis using DNA microarrays was used to identify genes and processes affected 
      by these compounds. AMI and VA upregulated lipid metabolism, whereas processes 
      associated with extracellular matrix remodelling and inflammation were 
      downregulated. TET downregulated mitochondrial functions, lipid metabolism, and 
      fibrosis. Furthermore, on the basis of the transcriptomics data it was 
      hypothesized that all three compounds affect peroxisome proliferator 
      activated-receptor (PPAR) signaling. Application of PPAR reporter assays 
      classified AMI and VA as PPARgamma and triple PPARalpha/(beta/delta)/gamma agonist, respectively, 
      whereas TET had no effect on any of the PPARs. Some of the differentially 
      expressed genes were considered as potential candidate biomarkers to identify 
      PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions 
      (i.e. TET). Finally, comparison of our findings with publicly available 
      transcriptomics data showed that a number of processes altered in the mouse PCLS 
      was also affected in mouse livers and human primary hepatocytes exposed to known 
      PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms 
      of action of compounds altering lipid metabolism.
FAU - Szalowska, Ewa
AU  - Szalowska E
AD  - Cluster of Bioassays and Toxicology, RIKILT - Institute of Food Safety, 
      Wageningen University and Research Centre, Wageningen, The Netherlands.
FAU - van der Burg, Bart
AU  - van der Burg B
AD  - BDS BioDetection Systems, Amsterdam, The Netherlands.
FAU - Man, Hai-Yen
AU  - Man HY
AD  - BDS BioDetection Systems, Amsterdam, The Netherlands.
FAU - Hendriksen, Peter J M
AU  - Hendriksen PJ
AD  - Cluster of Bioassays and Toxicology, RIKILT - Institute of Food Safety, 
      Wageningen University and Research Centre, Wageningen, The Netherlands.
FAU - Peijnenburg, Ad A C M
AU  - Peijnenburg AA
AD  - Cluster of Bioassays and Toxicology, RIKILT - Institute of Food Safety, 
      Wageningen University and Research Centre, Wageningen, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140129
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (PPAR alpha)
RN  - 0 (PPAR gamma)
RN  - 0 (PPAR-beta)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - F8VB5M810T (Tetracycline)
RN  - N3RQ532IUT (Amiodarone)
SB  - IM
MH  - Amiodarone/*pharmacology
MH  - Animals
MH  - Enzyme Inhibitors/*pharmacology
MH  - Extracellular Matrix/drug effects/metabolism/pathology
MH  - Fatty Liver/chemically induced/*genetics/metabolism/pathology
MH  - Gene Expression/drug effects
MH  - Gene Expression Profiling
MH  - Hepatocytes/drug effects/metabolism/pathology
MH  - Humans
MH  - Lipid Metabolism/*drug effects
MH  - Liver/*drug effects/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/drug effects/metabolism/pathology
MH  - Models, Biological
MH  - Oligonucleotide Array Sequence Analysis
MH  - PPAR alpha/agonists/genetics/metabolism
MH  - PPAR gamma/agonists/genetics/metabolism
MH  - PPAR-beta/agonists/genetics/metabolism
MH  - Tetracycline/*pharmacology
MH  - Tissue Culture Techniques
MH  - Transcriptome
MH  - Valproic Acid/*pharmacology
PMC - PMC3906077
COIS- Competing Interests: Authors Bart van der Burg, Hai-Yen Man are affiliated with a 
      commercial company (BioDetection Systems) and we confirm that this affiliation 
      has not compromised the objectivity or validity of the research, analyses, or 
      interpretations in the paper. This does not alter our adherence to all the PLOS 
      ONE policies on sharing data and materials.
EDAT- 2014/02/04 06:00
MHDA- 2014/09/30 06:00
PMCR- 2014/01/29
CRDT- 2014/02/04 06:00
PHST- 2013/08/21 00:00 [received]
PHST- 2013/12/04 00:00 [accepted]
PHST- 2014/02/04 06:00 [entrez]
PHST- 2014/02/04 06:00 [pubmed]
PHST- 2014/09/30 06:00 [medline]
PHST- 2014/01/29 00:00 [pmc-release]
AID - PONE-D-13-34549 [pii]
AID - 10.1371/journal.pone.0086795 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 29;9(1):e86795. doi: 10.1371/journal.pone.0086795. eCollection 
      2014.