Role of the Cell Adhesome in Obesity-related Liver Diseases

项目概要： 现代化的一个后果是，人们采用了他们所需要的饮食。 适应性差，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聚集体。 肝脏的代谢失调是后遗症中的早期和突出缺陷， 了以下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 (EGP)，但完整的脂肪生成和脂质储存。这造成血液调节受损 葡萄糖和肝脏中不健康的脂肪堆积。肝纤维化与 胰岛素抵抗我们有令人信服的证据表明，细胞“粘附体”夫妇的变化， 肝细胞外基质与胰岛素抵抗粘附体由整合素αβ组成 异二聚体，其将细胞外信号传递到细胞所必需的蛋白质复合物， 适应他们的环境。我们发现，破坏粘附体， 整合素α1亚基或通过缺失细胞中的整合素连接激酶（ILK）来预防脂肪肝 在肥胖的老鼠身上。有趣的是，只有ILK缺失防止GP对胰岛素抑制的抗性。 拟议的研究将确定细胞粘附体如何与肝代谢偶联， 调控研究将使用遗传小鼠模型来测试以下假设：i）有害 ILK在饮食诱导的肥胖小鼠肝脏中的作用需要它与结合 ii）ILK缺失逆转饮食中预先存在的脂肪肝和IR- 诱导的肥胖小鼠;和iii）ILK需要Itgβ1用于其在DIO小鼠中的代谢作用。这些 假设将使用同位素方法来测量脂肪酸合成和肝脏 脂肪酸摄取、甘油三酯形成和输出，以及导管插入后的葡萄糖通量， 有意识的遗传小鼠模型。将从这些小鼠模型中分离肝细胞， 定义了整个生物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， 瘦小鼠和饮食诱导的肥胖小鼠的细胞粘附体对营养流的调节。 内质网和线粒体的功能测试将定义它们的作用 系统必需的脂肪酸合成和营养氧化分别。这些研究将 确定细胞粘附体在肥胖相关的肝脏代谢疾病中的作用， 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.