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| Status |
Public on Dec 15, 2017 |
| Title |
Induction of DNA methylation changes in primary human hepatocytes by valproic acid |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
Valproic acid (VPA) is a very potent anti-cancer and neuro-protective drug. However, exposure to VPA may cause accumulation of lipids in the liver which could result in the development of steatosis. As VPA is a fatty acid analogue, most of the performed studies focus on inhibition of the mitochondrial b-oxidation pathway as the possible mode of action. However, investigations exploring the contribution of other processes in particular by using whole genome studies in a relevant human liver model are limited. Furthermore, the contribution of gene expression regulation by DNA methylation changes and/or miRNA changes is hardly known. Therefore, in the present study, we investigated the effect of repetitive VPA exposure on primary human hepatocytes (PHH) on whole genome gene expression-, DNA methylation-, and miRNA changes, using microarrays and integrated data analyses. PHH were exposed to a non-cytotoxic dose of 15 mM VPA for 5 days daily thereby inducing accumulation of lipids. Part of the PHH was left untreated for an additional 3 days in order to study the persistence of changes. VPA modulated the expression of a number of nuclear receptors and their target genes, leading to disturbed fatty acid metabolism and - uptake, ultimately leading to accumulation of triglycerides in the liver which is the key event leading to steatosis. Part of the gene expression changes was epigenetically regulated. Furthermore, after terminating the treatment, the expression and DNA methylation changes of several genes remained persistent, indicating a permanent change in the PHH, causing steatosis development to continue and/or making the PHH more sensitive for steatosis development during a subsequent exposure.
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| Overall design |
Primary human hepatocytes were exposed to 15 mM of VPA in a 24 hour repeat-dose testing regime. Medium was changed daily thereby providing a new dose of VPA to the PHH each day. A bi-phasic treatment regime was applied, combining a 5-day VPA exposure with a subsequent 3-days washout period during which the PHH were exposed to medium only. 1% Ethanol was used as solvent control.
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| Contributor(s) |
van Breda SG |
| Citation(s) |
29154799 |
| |
| Submission date |
Jul 08, 2016 |
| Last update date |
Jan 19, 2018 |
| Contact name |
Simone G van Breda |
| E-mail(s) |
s.vanbreda@maastrichtuniversity.nl
|
| Phone |
0031433882127
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| Organization name |
Maastricht University
|
| Department |
Toxicogenomics
|
| Street address |
Universiteitssingel 50
|
| City |
Maastricht |
| State/province |
Limburg |
| ZIP/Postal code |
6229 ER |
| Country |
Netherlands |
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| Platforms (1) |
| GPL16284 |
NimbleGen Human DNA Methylation 2.1M Deluxe Promoter Array [100929_HG19_Deluxe_Prom_Meth_HX1] |
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| Samples (12)
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| GSM2228804 |
Primary human hepatocyte 5 days control replicate 1 |
| GSM2228805 |
Primary human hepatocyte 5 days control replicate 2 |
| GSM2228806 |
Primary human hepatocyte 5 days control replicate 3 |
| GSM2228807 |
Primary human hepatocyte 5 days 15 mM valproic acid replicate 1 |
| GSM2228808 |
Primary human hepatocyte 5 days 15 mM valproic acid replicate 2 |
| GSM2228809 |
Primary human hepatocyte 5 days 15 mM valproic acid replicate 3 |
| GSM2228810 |
Primary human hepatocyte 8 days control replicate 1 |
| GSM2228811 |
Primary human hepatocyte 8 days control replicate 2 |
| GSM2228812 |
Primary human hepatocyte 8 days control replicate 3 |
| GSM2228813 |
Primary human hepatocyte 5 days 15 mM valproic acid and 3 days medium replicate 1 |
| GSM2228814 |
Primary human hepatocyte 5 days 15 mM valproic acid and 3 days medium replicate 2 |
| GSM2228815 |
Primary human hepatocyte 5 days 15 mM valproic acid and 3 days medium replicate 3 |
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| This SubSeries is part of SuperSeries: |
| GSE84250 |
Induction of changes in primary human hepatocytes by valproic acid |
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| Relations |
| BioProject |
PRJNA328477 |
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