当前位置: X-MOL 学术Cell. Signal. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Impairment of energy sensors, SIRT1 and AMPK, in lipid induced inflamed adipocyte is regulated by Fetuin A
Cellular Signalling ( IF 4.8 ) Pub Date : 2017-10-10 , DOI: 10.1016/j.cellsig.2017.10.005
Mrittika Chattopadhyay , Sandip Mukherjee , Subhendu K. Chatterjee , Dipanjan Chattopadhyay , Snehasis Das , Subeer S. Majumdar , Satinath Mukhopadhyay , Sutapa Mukherjee , Samir Bhattarcharya

Although several reports demonstrated that accumulation of excess lipid in adipose tissue produces defects in adipocyte which leads to the disruption of energy homeostasis causing severe metabolic problems, underlying mechanism of this event remains yet unclear. Here we demonstrate that FetuinA (FetA) plays a critical role in the impairment of two metabolic sensors, SIRT1 and AMPK, in inflamed adipocytes of high fat diet (HFD) mice. A linear increase in adipocyte hypertrophy from 10 to 16 week was in tandem with the increase in FetA and that coincided with SIRT1 cleavage and decrease in pAMPK which adversely affects PGC1α activation. Knock down (KD) of FetA gene in HFD mice could significantly improve this situation indicating FetA's contribution in the damage of energy sensors in inflamed adipocyte. However, FetA effect was not direct, it was mediated through TNF-α which again is dependent on FetA as FetA augments TNF-α expression. FetA being an upstream regulator of TNF-α, its suppression prevented TNF-α mediated Caspase-1 activation and cleavage of SIRT1. FetA induced inactivation of PGC1α due to SIRT1 cleavage decreased PPARϒ, adiponectin, NRF1 and Tfam expression. All these together caused a significant fall in mitochondrial biogenesis and bioenergetics that disrupted energy homeostasis resulting loss of insulin sensitivity. Taken together, our findings revealed a new dimension of FetA, it not only induced inflammation in adipocyte but also acts as an upstream regulator of SIRT1 cleavage and AMPK activation. Intervention of FetA may be worthwhile to prevent metabolic imbalance that causes insulin resistance and type 2 diabetes.



中文翻译:

Fetuin A调节脂质诱导的发炎脂肪细胞中能量传感器SIRT1和AMPK的损伤

尽管一些报道表明脂肪组织中过多脂质的积累会在脂肪细胞中产生缺陷,从而导致能量稳态的破坏,从而引起严重的代谢问题,但该事件的潜在机制仍不清楚。在这里,我们证明FetuinA(FetA)在高脂饮食(HFD)小鼠发炎的脂肪细胞中两个代谢传感器SIRT1和AMPK的损伤中起关键作用。从10周到16周,脂肪细胞肥大的线性增加与FetA的增加同时发生,并且与SIRT1的切割和pAMPK的减少同时发生,这对PGC1α的激活产生不利影响。在HFD小鼠中击倒FetA基因(KD)可以显着改善这种情况,表明FetA在发炎的脂肪细胞中的能量传感器受损中发挥了作用。但是,FetA的作用不是直接的,它通过TNF-α介导,而TNF-α又依赖于FetA,因为FetA增加了TNF-α的表达。FetA是TNF-α的上游调节剂,其抑制作用阻止TNF-α介导的Caspase-1激活和SIRT1的裂解。FetA诱导的SIRT1裂解使PGC1α失活,降低了PPARϒ,脂联素,NRF1和Tfam的表达。所有这些共同导致线粒体生物发生和生物能学的显着下降,从而破坏了能量稳态,从而导致胰岛素敏感性下降。综上所述,我们的发现揭示了FetA的新维度,它不仅诱导脂肪细胞发炎,而且还充当SIRT1切割和AMPK激活的上游调节剂。FetA的干预可能对于预防引起胰岛素抵抗和2型糖尿病的代谢失衡可能是值得的。

更新日期:2017-10-10
down
wechat
bug