The Role of Akt2 in Hepatic Lipid Metabolism

描述(申请人提供)：2型糖尿病(T2 DM)在世界各地的发病率正在增加，使其成为当前最大的健康风险之一。2型糖尿病总是与胰岛素抵抗有关，胰岛素抵抗是代谢综合征的组成部分之一，还包括肥胖、非酒精性脂肪性肝病(NAFLD)和高血压。胰岛素抵抗与代谢综合征的许多并发症有关，特别是称为糖尿病血脂异常的致动脉粥样硬化性脂质异常。然而，胰岛素抵抗如何导致血脂异常的机制尚不清楚。蛋白激酶Akt2/PKB-β是胰岛素正常代谢活动的主要介体，缺乏Akt2的小鼠由于胰岛素信号转导缺陷而出现糖耐量异常，但尚未对其脂代谢进行研究。我已经确定，当进入瘦素缺乏的ob/ob背景时，Akt2缺陷的小鼠与ob/ob小鼠相比，肝脏显著降低，但血清甘油三酯升高。这一观察结果表明，Akt2是维持正常脂平衡所必需的，本研究的目的是探讨Akt2在胰岛素依赖型脂代谢中的作用。这些研究的第一部分将调查Akt2的缺失如何导致正常肝脏脂质流量的失调。它将包括旨在确定Akt2基因缺失小鼠与肥胖和NAFLD模型杂交时脂肪生成、极低密度脂蛋白输出、脂肪酸酯化和β-氧化状态的生理学实验。此外，还将研究Akt2在脂质代谢中发挥作用的信号通路。这些研究的第二部分将检验这样一种假设，即这些脂代谢缺陷是由于肝细胞中Akt2的丢失所致。两种不同的肝脏缺乏Akt2的小鼠模型将被用来阐明肝脏Akt2表达的缺失是否会扰乱正常的脂肪代谢。此外，这一目标将决定Akt2是否可以单独在肝脏中逆转ob/ob Akt2缺失动物中观察到的肝脏甘油三酯缺乏的情况。最终，这些研究将进一步深入了解胰岛素对正常脂肪代谢的控制，并促进对这些过程在疾病中如何失调的了解。糖尿病是公共健康的最大威胁之一，因为患有这种疾病的患者越来越多。糖尿病与心脏病密切相关，而这种联系似乎与身体对脂肪的使用有关。这项提案中描述的研究旨在调查脂肪在体内的正常使用方式，以及在糖尿病存在时这些过程是如何被扰乱的，这可能会导致心脏病。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is increasing in incidence around the world, making it one of the greatest current health risks. T2DM is invariably associated with insulin resistance, one of the components of the Metabolic Syndrome, also comprised of obesity, non-alcoholic fatty liver disease (NAFLD) and hypertension. Insulin resistance is associated with many complications of the Metabolic Syndrome, specifically the atherogenic lipid abnormalities called diabetic dyslipidemia. However, the mechanism of how insulin resistance causes the development of dyslipidemia is unknown. The protein kinase, Akt2/PKB-beta is a major mediator of insulin's normal metabolic actions, and mice lacking Akt2 are glucose intolerant due to defects in insulin signaling, but have not been studied with regards to lipid metabolism. I have determined that when crossed onto a leptin-deficient ob/ob background, Akt2 deficient mice have dramatically decreased hepatic but increased serum triglycerides compared with ob/ob mice. This observation suggests that Akt2 is required for normal lipid homeostasis, and the goal of this proposal is to address the role of Akt2 in insulin-dependent lipid metabolism. The first portion of these studies will investigate how loss of Akt2 leads to a dysregulation of normal hepatic lipid flux. It will include physiological experiments aimed at determining the states of lipogenesis, VLDL export, fatty acid esterification and beta-oxidation in the Akt2 null mouse when crossed with models of obesity and NAFLD. In addition, the signaling pathways through which Akt2 exerts its effects on lipid metabolism will be studied. The second portion of these studies will test the hypothesis that these defects in lipid metabolism are due to a loss of Akt2 specifically in the hepatocytes. Two different mouse models lacking Akt2 in the liver will be used to elucidate whether loss of hepatic Akt2 expression disrupts normal lipid metabolism. Additionally, this aim will determine whether Akt2 in the liver alone can reverse the lack of hepatic triglyceride accumulation observed in the ob/ob Akt2 null animals. Ultimately, these studies will provide further insight into insulin's control of normal lipid metabolism, and advance the knowledge of how these processes are dysregulated in disease. Diabetes is one of the greatest dangers to public health due to the increasing numbers of patients with this condition. Diabetes is strongly associated with heart disease, and this connection appears to be related to the body's use of fat. The research described in this proposal aims to investigate how fat is normally used in the body, and how these processes are disrupted in the presence of diabetes, potentially leading to heart disease.