title: Study of Valproic Acid-Enhanced Hepatocyte Steatosis.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung 813, Taiwan.
authors.forename: Renin
authors.initials: R
authors.lastname: Chang
authors.affiliation: Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Pingtung Branch, No. 1, Anpin 1st Lane, Jhaosheng Road, Longtan Village, Neipu Township, Pingtung County 912, Taiwan.
authors.forename: Mei-Chia
authors.initials: MC
authors.lastname: Chou
authors.affiliation: Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec. 3, Keelung Road, Taipei 106, Taiwan.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Hung
authors.affiliation: Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec. 3, Keelung Road, Taipei 106, Taiwan.
authors.forename: Mu-En
authors.initials: ME
authors.lastname: Wang
authors.affiliation: Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec. 3, Keelung Road, Taipei 106, Taiwan.
authors.forename: Meng-Chieh
authors.initials: MC
authors.lastname: Hsu
authors.affiliation: Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec. 3, Keelung Road, Taipei 106, Taiwan.
authors.forename: Chih-Hsien
authors.initials: CH
authors.lastname: Chiu
mesh_terms: D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000096:biosynthesis; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics; D000070780:Perilipin-2 / Q000096:biosynthesis; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; C475476:LRP1 protein, human; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C000602982:PLIN2 protein, human; D047495:PPAR gamma; D000070780:Perilipin-2; D014280:Triglycerides; D014635:Valproic Acid; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase