Alhusaini Saif, McGee Kirsty, Schisano Bruno, Harte Alison, McTernan Philip, Kumar Sudhesh, Tripathi Gyanendra
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, United Kingdom.
Biochem Biophys Res Commun. 2010 Jul 2;397(3):472-8. doi: 10.1016/j.bbrc.2010.05.138. Epub 2010 May 31.
Recent findings indicate that endoplasmic reticulum (ER) stress is significantly increased in adipose tissue of obese human subjects and is critical to the initiation and integration of pathways of inflammation and insulin action. But the factors inducing ER stress in human adipose tissue are unknown. The common factors increased in obesity and linked to insulin resistance are hyperglycaemia, hyperlipidemia and also endotoxemia. Therefore, our aims were to investigate: (1) the role of lipopolysaccharide (LPS), high glucose (HG) and saturated fatty acids (SFA) as inducers of ER stress in primary human adipocytes and (2) whether salicylate, a known anti-inflammatory compound, can alleviate this effect. Components of the ER stress pathways were studied in human abdominal subcutaneous (AbSc) adipose tissue (AT) from obese and lean. Following the culture and differentiation of primary human preadipocytes, these adipocytes were treated with LPS, HG, tunicamycin (Tun) and SFA either alone or in combination with sodium salicylate (Sal). Markers of ER stress were significantly increased in AbSc AT of obese. Differentiated human adipocytes treated with LPS, Tun, HG and SFA showed significant activation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and activating transcription factor 6 (ATF6) and their down-stream targets. Sal alleviated this effect and activated AktSer473 phosphorylation. This study presents important evidence that: (1) there is increased ER stress in adipose tissue of obese individuals, (2) LPS, hyperglycaemia and saturated fatty acids induce significant ER stress in primary human adipocytes and (3) this induction is alleviated by salicylate.
最近的研究结果表明，内质网（ER）应激在肥胖人类受试者的脂肪组织中显著增加，并且对于炎症和胰岛素作用途径的启动和整合至关重要。但是，诱导人类脂肪组织内质网应激的因素尚不清楚。肥胖中增加且与胰岛素抵抗相关的常见因素是高血糖、高血脂以及内毒素血症。因此，我们的目的是研究：（1）脂多糖（LPS）、高糖（HG）和饱和脂肪酸（SFA）作为原代人脂肪细胞内质网应激诱导剂的作用，以及（2）已知的抗炎化合物水杨酸盐是否可以减轻这种作用。在内质网应激途径的组成部分在肥胖和瘦的人的腹部皮下（AbSc）脂肪组织（AT）中进行了研究。在原代人前脂肪细胞培养和分化后，这些脂肪细胞单独或与水杨酸钠（Sal）联合用LPS、HG、衣霉素（Tun）和SFA处理。内质网应激标志物在肥胖者的AbSc AT中显著增加。用LPS、Tun、HG和SFA处理的分化的人脂肪细胞显示真核翻译起始因子2α（eIF2α）和活化转录因子6（ATF6）及其下游靶点的显著激活。Sal减轻了这种作用并激活了AktSer473磷酸化。这项研究提供了重要证据表明：（1）肥胖个体的脂肪组织中内质网应激增加；（2）LPS、高血糖和饱和脂肪酸在原代人脂肪细胞中诱导显著的内质网应激；（3）水杨酸盐可减轻这种诱导作用。
