Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis.
Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis.
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Fas凋亡抑制分子缺失导致自发性肥胖和肝脂肪变性
DOI：
10.1038/cddis.2016.12
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发表时间：
2016-02-11
影响因子：
9
通讯作者：
Lam KP
中科院分区：
文献类型：
--
作者：
Huo J;Ma Y;Liu JJ;Ho YS;Liu S;Soh LY;Chen S;Xu S;Han W;Hong A;Lim SC;Lam KP
肝脏脂肪生成改变与肥胖和肝骨病等代谢性疾病有关。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细胞凋亡蛋白，在Akt信号转导中起中介作用。由于Akt在胰岛素信号转导的一个节点起作用，我们推测FAIM可能与能量代谢有关。在本研究中，C57BL/6野生型(WT)和非野生型(FAIM-KO)雄性小鼠以正常饲料喂养，并监测体重变化。用代谢笼分析能量消耗、底物利用和体力活动。取肝、胰腺和脂肪组织进行组织学检查。通过生化分析测定血糖、胰岛素水平和血脂水平。用免疫印迹法检测FAIM-KO小鼠胰岛素信号通路各成分的变化。我们发现，FAIM-KO小鼠出现了自发性非高血压性肥胖，并伴有肝骨病、脂肪细胞肥大、血脂异常、高血糖和高胰岛素血症。在FAIM-KO肝脏中，脂肪生成增加，表现为脂肪酸合成增加以及SREBP-1和SREBP-2激活。值得注意的是，在FAIM-KO小鼠的胰岛素靶器官中，胰岛素受体β的蛋白表达显著减少。FAIM-KO肝脏和脂肪组织中AKT的磷酸化水平也低于WT对照组。此外，胰岛素诱导的FAIM-KO肝细胞胰岛素受体底物-1和Akt2的磷酸化也明显减弱。综上所述，我们的数据表明，FAIM是一种新的胰岛素信号调节因子，在能量稳态中发挥着重要作用。这些发现可能有助于阐明肥胖和肝骨病的发病机制。
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.