Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model.
Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model.
复制标题
DOI：
10.33594/000000206
复制
发表时间：
2020-01-24
期刊：
影响因子：
--
通讯作者：
de Frutos, Sergio
中科院分区：
文献类型：
--
作者：
Hatem-Vaquero, Marco;Griera, Mercedes;de Frutos, Sergio
背景/目标：2型糖尿病、代谢综合征或非酒精性脂肪肝是胰岛素抵抗相关的代谢紊乱，在完全建立之前缺乏更好的预后。我们研究了细胞内支架蛋白整合素连接激酶（ILK）作为一个关键的调制器在最初的发病机制和早期进展的胰岛素抵抗相关disorders.METHODS：成年小鼠与全球转基因下调ILK的表达（cKD-ILK）和同窝出生的人没有消耗（CT）的标准（STD）或高脂肪（HFD）饮食在2和6周。在禁食条件下和腹膜内注射葡萄糖或丙酮酸盐后测定动物的体重、血糖和其他全身生化参数，以测试其耐受性。在从胰岛素敏感组织提取的RNA或蛋白质中，我们通过逆转录-定量PCR和蛋白质印迹法测定ILK、代谢物转运蛋白和其他代谢和炎症标志物的表达。在新鲜分离的tissues.RESULTS葡萄糖摄取能力进行了研究：HFD喂养是能够早期和进行性增加高血糖症，胰岛素血症，循环甘油，体重增加，肝脏介导的血管生成沿着这段时间的推移，但cKD-ILK有所有这些系统的失衡加剧相比，CT在相同的HFD时间的推移。有趣的是，HFD喂养的CT中ILK的组织表达在白色脂肪组织（WAT）、骨骼肌和肝脏中显著下调，其程度与cKD-ILK的原始ILK下调相同。我们先前发表了基础STD喂养的cKD-ILK与基础STD-CT相比在WAT和骨骼肌中具有不同的葡萄糖转运蛋白GLUT 4表达。在相同的STD喂养的cKD-ILK中，我们观察到肝脏GLUT 2和WAT促炎细胞因子TNF-α和MCP-1的表达增加。HFD的给药加剧了cKD-ILK中这些和其他与观察到的不平衡代谢相关的标志物的表达变化，如WAT脂解（HSL）、肝细胞生成（PCK-1）和甘油转运（AQP 9）。ILK表达可作为代谢紊乱建立的预测性决定因素，因为它的下调似乎与葡萄糖和甘油转运的早期不平衡以及随后这些代谢物的全身稳态的丧失相关。
BACKGROUND/AIMS: Diabetes type 2, metabolic syndrome or non-alcoholic fatty liver disease are insulin resistance-related metabolic disorders, which lack a better prognosis before their full establishment. We studied the importance of the intracellular scaffold protein integrin linked kinaes (ILK) as a key modulator in the initial pathogenesis and the early progression of those insulin resistance- related disorders.METHODS: Adult mice with a global transgenic downregulation of ILK expression (cKD-ILK) and littermates without that depletion (CT) were fed with either standard (STD) or high fat (HFD) diets during 2 and 6 weeks. Weights, blood glucose and other systemic biochemical parameters were determined in animals under fasting conditions and after glucose or pyruvate intraperitoneal injections to test their tolerance. In RNA or proteins extracted from insulin-sensitive tissues, we determined by reverse transcription-quantitative PCR and western blot the expression of ILK, metabolites transporters and other metabolism and inflammatory markers. Glucose uptake capacity was studied in freshly isolated tissues.RESULTS: HFD feeding was able to early and progressively increase glycaemia, insulinemia, circulating glycerol, body weight gain, liver-mediated gluconeogenesis along this time lapse, but cKD-ILK have all these systemic misbalances exacerbated compared to CT in the same HFD time lapse. Interestingly, the tisular expression of ILK in HFD-fed CT was dramatically downregulated in white adipose tissue (WAT), skeletal muscle and liver at the same extent of the original ILK downregulation of cKD-ILK. We previously published that basal STD-fed cKD-ILK compared to basal STD-CT have different expression of glucose transporters GLUT4 in WAT and skeletal muscle. In the same STD-fed cKD-ILK, we observed here the increased expressions of hepatic GLUT2 and WAT pro-inflammatory cytokines TNF-alpha and MCP-1. The administration of HFD exacerbated the expression changes in cKD-ILK of these and other markers related to the imbalanced metabolism observed, such as WAT lipolysis (HSL), hepatic gluconeogenesis (PCK-1) and glycerol transport (AQP9).CONCLUSION: ILK expression may be taken as a predictive determinant of metabolic disorders establishment, because its downregulation seems to correlate with the early imbalance of glucose and glycerol transport and the subsequent loss of systemic homeostasis of these metabolites.