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首页> 外文期刊>Cell death & disease. >Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis
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Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis

机译：Fas凋亡抑制分子的丢失导致自发性肥胖和肝脂肪变性

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Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.
机译：肝脂肪形成的改变与代谢性疾病如肥胖和肝脂肪变性有关。胰岛素抵抗和代偿性高胰岛素血症是这些代谢失衡的关键驱动因素。 Fas凋亡抑制分子（FAIM）是一种普遍表达的抗凋亡蛋白，可作为Akt信号传导的介体。由于Akt在胰岛素信号转导中起作用，因此我们假设FAIM可能参与能量代谢。在当前的研究中，给C57BL / 6野生型（WT）和FAIM基因敲除（FAIM-KO）雄性小鼠喂食正常的食物，并监测其体重变化。使用代谢笼分析能量消耗，底物利用率和体育活动。对肝，胰腺和脂肪组织进行组织学检查。通过生化测定确定血清葡萄糖和胰岛素水平以及脂质分布。通过免疫印迹检查FAIM-KO小鼠中胰岛素信号传导途径的成分变化。我们发现，FAIM-KO小鼠发展为自发性非高脂血症性肥胖症，并伴有肝脂肪变性，脂肪细胞肥大，血脂异常，高血糖症和高胰岛素血症。在FAIM-KO肝脏中，脂肪合成增加，脂肪酸合成增加，SREBP-1和SREBP-2激活。值得注意的是，FAIM-KO小鼠的胰岛素靶器官中胰岛素受体β的蛋白质表达明显降低。与野生型对照相比，FAIM-KO肝脏和脂肪组织中的Akt磷酸化水平也较低。另外，在分离的FAIM-KO肝细胞中，响应于胰岛素处理的胰岛素受体底物1和Akt2的磷酸化也显着减弱。总而言之，我们的数据表明FAIM是一种新型的胰岛素信号调节剂，在能量稳态中起着至关重要的作用。这些发现可能为肥胖和肝脂肪变性的发病机理提供启示。

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