Induction of changes in primary human hepatocytes by valproic acid
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ABSTRACT:
PROVIDER: PRJNA328467 | ENA |
REPOSITORIES: ENA
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Project description: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.
2017-12-15 | GSE84239 | GEO
Project description: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.
2017-12-15 | GSE84189 | GEO
Project description: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.
2017-12-15 | GSE84150 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-12-15 | GSE84250 | GEO
Project description:Transcriptional profiling of valproic acid and valproic acid analogs in human embryonic stem cells.
2010-12-31 | E-MEXP-2374 | biostudies-arrayexpress
Project description:Myristic acid, the 14-carbon saturated fatty acid (C14:0), is usually associated with negative consequences for human health, and in particular its consumption is correlated to an increased cardiovascular disease risk. Since it is a little abundant into the cells, its specific properties and functional roles have not been fully described. The aim of this study was to explore the cell response to this fatty acid to help explaining clinical findings on the relationship between C14:0 and cardiovascular disease. Primary murine hepatocytes were used as a model to investigate the hepatic response to C14:0 in a proteomic approach. C14:0 treatment (250 µM) of primary murine hepatocytes confirmed that myristic acid induces lipid droplet accumulation as shown by cellular imaging and elevated perilipin 2 levels on cellular proteome level. The functionally enriched pathways were involved in protein synthesis, transport and degradation, protein depalmitoylation, unfolded protein response, lipid and cholesterol metabolism, mitophagy in response to depolarization, and cell cell adhesion. Our data provide for the first time quantitative proteomic data regarding C14:0 in primary murine hepatocytes (M1 in present dataset) and contribute to the elucidation of the molecular mechanisms through which this fatty acid can cause adverse health effects.
2022-03-01 | PXD009017 | Pride
Project description:The goal of this study is to define genes that are differentially expressed in Down syndrome leukemic blasts after treatment with valproic acid (VPA) Here we report the identification gene sets that are downregulated in Down syndrome leukemic cell lines after exposure to valproic acid (VPA)
2011-07-13 | GSE30517 | GEO
Project description:The purpose of this study is to first determine the maximum tolerated dose of capecitabine given alone or in combination with valproic acid during preoperative short-course radiotherapy (Phase 1). The next part of the study (Phase 2)will explore whether the addition of valproic acid or the addition of capecitabine to short-course radiotherapy, before optimal radical surgery might increase the pathologic complete tumor regression rate in patients with low-moderate risk rectal cancer.
| 2148214 | ecrin-mdr-crc
Project description:Valproic acid (VA) is a small-chain branched fatty acid, widely used as anticonvulsant, and mood stabilizer to treat psychiatric illness. Valproic acid is also known to inhibit the histone deacetylases (HDACs), which makes it as a potent antitumor agent in alone or in combination with other cytotoxic drugs. Beside its conventional activities, valproic acid reported to have much broader, complicated effects and affect many complex physiological processes. However the molecular mechanisms of valproic acid are unclear. So, we used budding yeast transcriptome analysis to better understand the molecular mechanism of action of valproic acid. The clusters of differentially expressed genes in microarray after VA (6mM) treatment and their functional enrichment analysis revealed its overall effects on various biological processes such as cell cycle, signal transduction, metabolism, transcription, ubiquitination, transporter activities and many more. The microarray data were validated by quantitative real-time PCR.
2016-10-14 | GSE62400 | GEO
Project description:Transcriptional profiling of human placenta-derived JEG-3 cell line comparing vehicle control with 7.38 mM of valproic acid(VPA)-treated JEG-3 cells for 48 hr. 7.38 mM valproic acid(VPA) induced the 30% inhibiotion of JEG-3 cell proliferation, G1 phase cell cycle arrest and the reduction of cell size. The Goal was to analyze the mechanism of valproic acid-induced adverse effects in placental cells.
2012-10-11 | GSE41441 | GEO