Ju Liping, Zhang Xiaoyan, Deng Yujie, Han Junfeng, Yang Jian, Chen Shuqin, Fang Qichen, Yang Ying, Jia Weiping
Shanghai Key Laboratory of Diabetes, Shanghai Institute for Diabetes, Shanghai Clinical Medical Centre of Diabetes, Shanghai Key Clinical Centre of Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Jiao-Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Endocrine and Metabolic Diseases, Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2017 Jan 5;8(1):e2533. doi: 10.1038/cddis.2016.439.
Although precisely controlled lipolysis is crucial for maintaining physiological levels of circulating free fatty acids in response to energetic stress, the underlying mechanisms by which this process is governed remain poorly understood. Survivin is a gene that has been found to be highly expressed in the most common human tumors, and it is considered to be associated with tumorigenesis. Survivin expression in normal tissue is developmentally downregulated and is undetectable in most terminally differentiated adult tissues. Here, we report that Survivin expression in mature adipocytes from murine white adipose tissue can be highly induced under high-fat diet feeding conditions. During the adipocyte differentiation of 3T3-L1 preadipocytes and mesenchymal C3H10T1/2 cells, Survivin expression is gradually decreased and almost undetectable in fully differentiated adipocytes. However, it can be expressed again upon insulin exposure, through the PI3K/mTOR signaling pathway. Nevertheless, Survivin overexpression is sensitive to nutritional deprivation, and expression markedly decreases in response to starvation with Hank's buffered salt solution challenge. The ectopic expression of Survivin downregulates expression of Adrb3 and then decreases the production of cAMP, while Fsp27 protein levels are upregulated as a result of reduced protein degradation. This in turn inhibits isoproterenol-stimulated adipocyte lipolysis. Survivin also attenuates DNA damage related to PARP activation and inhibits TNFα-induced lipolysis, suggesting that Survivin may facilitate adipocyte maintenance in response to inflammatory stimuli. Further studies will be undertaken to determine whether Survivin is critical for lipid storage to maintain metabolic homeostasis in vivo.
尽管精确调控的脂肪分解对于在能量应激时维持循环游离脂肪酸的生理水平至关重要，但该过程的潜在调控机制仍知之甚少。Survivin是一种在最常见的人类肿瘤中高表达的基因，被认为与肿瘤发生有关。Survivin在正常组织中的表达在发育过程中下调，在大多数终末分化的成年组织中无法检测到。在此，我们报告，在高脂饮食喂养条件下，小鼠白色脂肪组织成熟脂肪细胞中的Survivin表达可被高度诱导。在3T3-L1前脂肪细胞和间充质C3H10T1/2细胞的脂肪细胞分化过程中，Survivin表达逐渐降低，在完全分化的脂肪细胞中几乎无法检测到。然而，在胰岛素暴露后，它可通过PI3K/mTOR信号通路再次表达。尽管如此，Survivin过表达对营养剥夺敏感，在汉克缓冲盐溶液刺激饥饿时，其表达明显降低。Survivin的异位表达下调Adrb3的表达，进而降低cAMP的产生，而Fsp27蛋白水平因蛋白降解减少而上调。这反过来又抑制异丙肾上腺素刺激的脂肪细胞脂肪分解。Survivin还减轻与PARP激活相关的DNA损伤，并抑制TNFα诱导的脂肪分解，表明Survivin可能有助于脂肪细胞在炎症刺激下的维持。将进行进一步研究以确定Survivin对于体内脂质储存以维持代谢稳态是否至关重要。
