title: Suppression of adipogenesis by valproic acid through repression of USF1-activated fatty acid synthesis in adipocytes.
abstract: VPA (valproic acid), a short-chain fatty acid that is a HDAC (histone deacetylase) inhibitor, is known to suppress adipogenesis. In the present study, we identified the molecular mechanism of VPA-mediated suppression of adipogenesis in adipocytes. VPA suppressed the accumulation of intracellular triacylglycerol. The expression levels of PPARγ (peroxisome-proliferator-activated receptor γ) and C/EBPα (CCAAT/enhancer-binding protein α), which are key regulators of adipogenesis, as well as the expression of SCD (stearoyl-CoA desaturase), were decreased by the treatment with VPA. Moreover, glycerol release was decreased in the VPA-treated cells, even though the transcription levels of ATGL (adipose triacylglycerol lipase), HSL (hormone-sensitive lipase) and MGL (monoacylglycerol lipase), all of which are involved in lipolysis, were elevated by the treatment with VPA. It is noteworthy that the expression level of FAS (fatty acid synthase) was significantly suppressed when the cells were cultured in medium containing VPA. Furthermore, VPA-mediated suppression of the accumulation of the intracellular triacylglycerols was prevented by the treatment with palmitic acid, a major product of FAS. The results of promoter-luciferase and chromatin immunoprecipitation assays demonstrated that USF1(upstream stimulating factor 1) bound to the E-box of the promoter region of the FAS gene. In addition, the expression of USF1 was decreased by the treatment with VPA. siRNA-mediated knockdown of the expression of the USF1 gene repressed adipogenesis along with the decreased expression of the FAS gene. The overexpression of USF1 enhanced both adipogenesis and the expression of FAS in VPA-treated cells. These results indicate that VPA suppressed adipogenesis through the down-regulation of USF1-activated fatty acid synthesis in adipocytes.
authors: *Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors: Miki
authors: M
authors: Yuyama
authors: *Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors: Ko
authors: K
authors: Fujimori
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis; D051720:Upstream Stimulatory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014280:Triglycerides; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D019308:Palmitic Acid; D014635:Valproic Acid; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D054890:Fatty Acid Synthase, Type I