Study of Valproic Acid-Enhanced Hepatocyte Steatosis

Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell l...

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Autores principales: Chang, Renin, Chou, Mei-Chia, Hung, Li-Ying, Wang, Mu-En, Hsu, Meng-Chieh, Chiu, Chih-Hsien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789392/
https://www.ncbi.nlm.nih.gov/pubmed/27034954
http://dx.doi.org/10.1155/2016/9576503
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author Chang, Renin
Chou, Mei-Chia
Hung, Li-Ying
Wang, Mu-En
Hsu, Meng-Chieh
Chiu, Chih-Hsien
author_facet Chang, Renin
Chou, Mei-Chia
Hung, Li-Ying
Wang, Mu-En
Hsu, Meng-Chieh
Chiu, Chih-Hsien
author_sort Chang, Renin
collection PubMed
description Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA-) induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG) synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36), low-density lipoprotein receptor-related protein 1 (Lrp1), diacylglycerol acyltransferase 2 (Dgat2), and perilipin 2 (Plin2) were increased, that of carnitine palmitoyltransferase I a (Cpt1a) was not affected, and those of acetyl-Co A carboxylase α (Acca) and fatty acid synthase (Fasn) were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ) nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation.
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spelling pubmed-47893922016-03-31 Study of Valproic Acid-Enhanced Hepatocyte Steatosis Chang, Renin Chou, Mei-Chia Hung, Li-Ying Wang, Mu-En Hsu, Meng-Chieh Chiu, Chih-Hsien Biomed Res Int Research Article Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA-) induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG) synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36), low-density lipoprotein receptor-related protein 1 (Lrp1), diacylglycerol acyltransferase 2 (Dgat2), and perilipin 2 (Plin2) were increased, that of carnitine palmitoyltransferase I a (Cpt1a) was not affected, and those of acetyl-Co A carboxylase α (Acca) and fatty acid synthase (Fasn) were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ) nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation. Hindawi Publishing Corporation 2016 2016-02-29 /pmc/articles/PMC4789392/ /pubmed/27034954 http://dx.doi.org/10.1155/2016/9576503 Text en Copyright © 2016 Renin Chang et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Chang, Renin
Chou, Mei-Chia
Hung, Li-Ying
Wang, Mu-En
Hsu, Meng-Chieh
Chiu, Chih-Hsien
Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title_full Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title_fullStr Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title_full_unstemmed Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title_short Study of Valproic Acid-Enhanced Hepatocyte Steatosis
title_sort study of valproic acid-enhanced hepatocyte steatosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789392/
https://www.ncbi.nlm.nih.gov/pubmed/27034954
http://dx.doi.org/10.1155/2016/9576503
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