Role of the Cell Adhesome in Obesity-related Liver Diseases

项目总结： 现代化的一个结果是，人们采用了他们应得的饮食 适应能力差，生活方式不活跃。这导致了肥胖症的急剧增加， 血脂异常、2型糖尿病以及代谢综合征的其他集合体。 肝脏代谢失调是后遗症中的一个早期和突出的缺陷，导致 这些条件。肝脏明显的主要缺陷是选择性胰岛素抵抗。 以内源性葡萄糖产生的胰岛素抑制受损为特征的 (EGP)，但完整的脂肪生成和脂肪储存。这就造成了血液调节受损。 葡萄糖和肝脏中不健康的脂肪堆积。肝纤维化与肝纤维化密切相关 胰岛素抵抗。我们有令人信服的证据表明，细胞中“粘性”夫妇的变化。 肝脏细胞外基质对胰岛素抵抗的影响。粘附物由整合素αβ组成 将细胞外信号传递给细胞所需的蛋白质复合体的异源二聚体 适应他们的环境。我们发现，对粘性物质的破坏要么是通过破坏 整合素α1亚单位或通过细胞内整合素连接激酶(ILK)的缺失来预防脂肪肝 在肥胖的小鼠身上。有趣的是，只有ilk缺失才能防止GP对胰岛素抑制的抵抗。 拟议的研究将定义细胞黏附如何与肝脏新陈代谢相结合。 监管。研究将使用遗传小鼠模型来检验以下假设：1)有害 ILK在饮食诱导的肥胖小鼠肝脏中的作用需要与结合形成络合物 伙伴，Pinch和Parvin；ii)ilk缺失逆转了饮食中先前存在的脂肪肝和IR- ILK需要Itgβ1才能在DIO小鼠体内发挥代谢作用。这些 假说将使用同位素方法来测量脂肪酸合成和肝脏。 导尿管对脂肪酸的摄取、甘油三酯的形成和输出，以及葡萄糖的通量， 有意识的遗传小鼠模型。将从这些小鼠模型中分离出肝细胞以 定义在整个有机体中特别复杂的机制。生化和 组织学分析将确定参与代谢的途径和调节机制 瘦肉型和食源性肥胖小鼠细胞黏附对营养素通量的调节。 内质网和线粒体的功能测试将确定这些 分别对脂肪酸合成和营养物质氧化至关重要的系统。这些研究将 确定细胞黏附在肥胖相关的肝脏代谢疾病中的作用，它将识别 治疗肥胖对肝脏代谢影响的潜在靶点。

PROJECT SUMMARY: A consequence of modernization is that people have adopted diets for which they are poorly adapted and live inactive lifestyles. This has resulted in dramatic increases in obesity, dyslipidemias, Type 2 diabetes, as well as other aggregates of the Metabolic Syndrome. Metabolic dysregulation of the liver is an early and prominent defect in the sequalae that lead to these conditions. A primary defect evident in the liver is a selective insulin resistance characterized by an impairment in insulin suppression of endogenous glucose production (EGP), but intact lipogenesis and lipid storage. This creates impaired regulation of blood glucose and an unhealthy accumulation of fat in the liver. Liver fibrosis is closely correlated to insulin resistance. We have compelling evidence that the cell “adhesome” couples changes in liver extracellular matrix to insulin resistance. The adhesome consists of integrin αβ heterodimers that transmit extracellular signals to protein complexes necessary for cells to adapt to their environment. We found that disruption of the adhesome either by disrupting the integrin α1 subunit or by deletion of the integrin-linked kinase (ILK) in the cell prevents fatty liver in obese mice. Interestingly, only ILK deletion prevents resistance to insulin suppression of GP. The proposed studies will define how the cell adhesome is coupled to hepatic metabolic regulation. Studies will use genetic mouse models to test the hypotheses that i) deleterious effects of ILK in the liver of diet-induced obese mice require that it complex with binding partners, PINCH and parvin; ii) ILK deletion reverses pre-existing fatty liver and IR in diet- induced obese mice; and iii) ILK requires Itgβ1 for its metabolic effects in DIO mice. These hypotheses will be addressed using isotopic methods to measure fatty acid synthesis and liver fatty acid uptake, triglyceride formation and export, and glucose fluxes in catheterized, conscious genetic mouse models. Hepatocytes will be isolated from these mouse models to define mechanisms that are particularly complex in the whole organism. Biochemical and histological analyses will identify pathways and regulatory mechanisms involved in metabolic regulation of nutrient fluxes by the cell adhesome of lean and diet-induced obese mice. Functional tests of the endoplasmic reticulum and mitochondria will define the role of these systems essential to fatty acid synthesis and nutrient oxidation, respectively. These studies will define the role of the cell adhesome in obesity-related liver metabolic disease and it will identify potential targets for treating the metabolic effects of obesity on the liver.