*Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Biochem J. 2014 May 1;459(3):489-503. doi: 10.1042/BJ20131476.
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.
VPA（丙戊酸）是一种短链脂肪酸，作为 HDAC（组蛋白去乙酰化酶）抑制剂，已被证实可抑制脂肪生成。在本研究中，我们确定了 VPA 抑制脂肪细胞脂肪生成的分子机制。VPA 抑制细胞内三酰基甘油的积累。PPARγ（过氧化物酶体增殖物激活受体 γ）和 C/EBPα（CCAAT/增强子结合蛋白 α）的表达水平，这两种物质是脂肪生成的关键调节剂，以及 SCD（硬脂酰辅酶 A 去饱和酶）的表达水平，均被 VPA 处理所下调。此外，即使 VPA 处理后脂肪酶基因（ATGL、HSL 和 MGL）的转录水平升高，甘油的释放也会减少，这三种酶均参与脂肪分解。值得注意的是，当细胞在含有 VPA 的培养基中培养时，FAS（脂肪酸合酶）的表达水平显著下调。此外，用棕榈酸处理可防止 VPA 介导的细胞内三酰基甘油积累。启动子-荧光素酶和染色质免疫沉淀分析的结果表明，USF1（上游刺激因子 1）结合到 FAS 基因启动子区域的 E 盒上。此外，VPA 处理会降低 USF1 的表达。siRNA 介导的 USF1 基因表达下调抑制了脂肪生成，同时也下调了 FAS 基因的表达。USF1 的过表达增强了 VPA 处理细胞的脂肪生成和 FAS 表达。这些结果表明，VPA 通过下调 USF1 激活的脂肪酸合成来抑制脂肪生成。
