【作者】 张日华；

【导师】 赵子建；

【作者基本信息】 南京医科大学 ， 病理学与病理生理学， 2013， 博士

【摘要】 肥胖日益成为严重影响人们健康和生活质量最常见的慢性疾病之一，给社会带来了沉重的负担。因此，进一步明确其发生发展的分子机制并筛查新的药物靶标对于控制肥胖及其并发症有着重要意义。S100A16属于S100家族的新成员，是一种小分子酸性Ca2+结合蛋白。S100A16蛋白广泛低表达于全身各组织，在食管组织中表达较高、其次是脂肪和结肠组织，在肝脏中表达较低。S100A16蛋白高表达于多种肿瘤组织。在我们的前期研究中，基因芯片筛查不同分化程度的脂肪细胞内多种基因的表达差异，结果显示，随着脂肪细胞分化程度的减弱，S100A16表达下调。因此，我们推测S100A16与脂肪细胞分化密切相关，并采用细胞与动物模型探讨S100A16对脂肪细胞分化和肥胖的作用以及分子机制。首先，我们以小鼠胚胎成纤维细胞系3T3-L1为模型，研究S100A16对脂质形成的作用及机制。其次，我们构建了四种小鼠模型：全身高表达S100A16的转基因小鼠（S100A16Tg-/+）、脂肪组织特异性高表达S100A16的转基因小鼠（aP2-S100A16Tg-/+）、全身敲除S100A16的基因敲除小鼠（S100A16KO+/-）、脂肪组织特异性敲除S100A16的基因敲除小鼠（Fabp-S100A16KO+/-），以研究在体内，S100A16对脂肪形成和胰岛素抵抗的作用。再者，分离原代小鼠胚胎成纤维细胞MEF，在此原代细胞模型基础上，进一步深入研究S100A16影响脂质形成的分子机制。S100A16促进脂肪细胞形成，上调脂肪细胞标志基因表达，促进前体脂肪细胞增值。S100A16促使成熟脂肪细胞的胰岛素刺激的葡萄糖摄取明显受到抑制，胰岛素刺激的信号转导通路也明显下调。S100A16与p53可能是间接结合，进而影响其功能，而S100B起到中介作用。因此，我们认为，S100A16是一种全新的促脂肪细胞生成因子。更多还原

【Abstract】 Obesity is one kind of common chronic diseases. Patients with obesity andassociated metabolic disturbances have a significantly increased risk of heart attackand stroke compared with people with normal weight. Differentiation ofpreadipocytes to adipocytes requires actions of transcription regulatory networks.S100A16is a member of S100protein super family that carries calcium-bindingEF-hand motifs. Its expression is ubiquitous and elevated in various types of tumors.Using3T3-L1preadipocyte model, S100A16transgenic mouse and knock outmouse modle, and MEFs cell modle, we investigated the expression and function ofS100A16during differentiation into adipocytes as well as the potential roles ofS100A16in the regulation of insulin sensitivity.We found that the expression of S100A16was increased during differentiation,and overexpression of S100A16in3T3-L1preadipocytes increased their proliferationand markedly enhanced adipogenesis, but resulted in significant reduction ofinsulin-stimulated glucose uptake and phosphoryltion of AKT. In contrast,suppression of S100A16expression with RNAi significantly inhibited adipogensisand preadipocyte proliferation. Immunoprecipitation analysis revealed that S100A16could physically interact with p53, also a known inhibitor of adipogenesis.Thus, we reveal for the first time that S100A16protein is a noveladipogenesis-promoting factor, and that increased expression of S100A16inadipocytes can have a negative impact on insulin sensitivity.更多还原