The Role of Akt2 in Hepatic Lipid Metabolism

Akt2 在肝脏脂质代谢中的作用

• 批准号: 7586822
• 负责人: Karla Fitzgerald Leavens
• 金额: $ 2.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586822
• 关键词: Accounting; Address; Adipocytes; Affect; Animals; Area; Cardiovascular Diseases; Cells; Characteristics; Complex; Country; Defect; Development; Diabetes Mellitus; Disease; Dyslipidemias; Esterification; Fatty Acids; Fatty acid glycerol esters; Future; Genes; Glucose; Goals; Hand; Health; Heart Diseases; Hepatic; Hepatocyte; Homeostasis; Hormones; Hypertension; Hypertriglyceridemia; Incidence; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Lead; Leptin; Link; Lipids; Liver; Liver diseases; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Mus; Muscle; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Process; Protein Kinase; Public Health; Regulation; Relative (related person); Research; Risk; Role; Secondary to; Series; Serum; Signal Pathway; Signal Transduction; Testing; Tissues; Triglycerides; Very low density lipoprotein; diabetic; improved; insight; insulin mediators; insulin signaling; lipid biosynthesis; lipid metabolism; mortality; mouse model; non-alcoholic fatty liver; oxidation; prevent; research study; uptake

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.

描述（由申请人提供）：2型糖尿病（T2 DM）在世界范围内的发病率正在增加，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相关，胰岛素抵抗是代谢综合征的组成部分之一，也包括肥胖、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脂质异常。然而，胰岛素抵抗导致血脂异常发生的机制尚不清楚。蛋白激酶Akt 2/PKB-β是胰岛素正常代谢作用的主要介质，缺乏Akt 2的小鼠由于胰岛素信号传导缺陷而葡萄糖不耐受，但尚未研究脂质代谢。我已经确定，当与瘦素缺乏的ob/ob背景杂交时，与ob/ob小鼠相比，Akt 2缺陷小鼠的肝脏甘油三酯显著降低，但血清甘油三酯升高。这一观察结果表明，Akt 2是正常的脂质稳态所必需的，该提案的目标是解决Akt 2在胰岛素依赖性脂质代谢中的作用。这些研究的第一部分将研究Akt 2的丢失如何导致正常肝脏脂质通量的失调。它将包括旨在确定与肥胖和NAFLD模型杂交时Akt 2敲除小鼠中脂肪生成、VLDL输出、脂肪酸酯化和β-氧化的状态的生理学实验。此外，还将研究Akt 2对脂质代谢发挥作用的信号通路。这些研究的第二部分将检验以下假设：脂质代谢中的这些缺陷是由于肝细胞中特定Akt 2的丢失所致。将使用两种不同的肝脏中缺乏Akt 2的小鼠模型来阐明肝脏Akt 2表达的丧失是否会破坏正常的脂质代谢。此外，该目的将确定单独的肝脏中的Akt 2是否可以逆转在ob/ob Akt 2缺失动物中观察到的肝脏甘油三酯积累的缺乏。最终，这些研究将进一步深入了解胰岛素对正常脂质代谢的控制，并推进这些过程在疾病中如何失调的知识。糖尿病是对公共卫生的最大威胁之一，因为患有这种疾病的患者数量越来越多。糖尿病与心脏病密切相关，这种联系似乎与身体对脂肪的使用有关。该提案中描述的研究旨在研究脂肪在体内的正常使用方式，以及这些过程在糖尿病存在时如何被破坏，从而可能导致心脏病。