Role of Hepatic FoxO1 in Atherosclerosis

描述（由申请人提供）：血脂异常，包括肝脏过度产生和分泌甘油三酯和胆固醇，是2型糖尿病的一种显著代谢异常，可导致动脉粥样硬化和冠状动脉疾病的发展。胰岛素抵抗和高血糖在这一过程的病理生理学中的相对作用尚不清楚，导致血脂异常的细胞事件也是如此。最近，人们发现转录因子FoxO 1除了在调节葡萄糖产生中的既定作用外，还在连接胰岛素信号传导与脂蛋白周转的途径中是重要的效应子。由于FoxO 1可受胰岛素（通过磷酸化依赖性失活）和葡萄糖（通过脱乙酰化依赖性激活）调节，因此我们推断FoxO 1功能异常可能为糖尿病血脂异常提供统一的机制。为了表征FoxO 1对脂蛋白代谢的贡献，我们将在两种不同的代谢应激条件下分析肝脏特异性FoxO 1敲除小鼠（L-FoxO 1）的脂质和胆固醇代谢：在目标1中，小鼠将被链脲佐菌素（STZ）致糖尿病，使我们能够检查FoxO 1在高血糖期间的作用。在目的2中，将L-FoxO 1和对照在动脉粥样硬化倾向菌株背景（LDLR-/-）上繁殖，并饲喂高脂肪、高胆固醇饮食，其中可以确定FoxO 1在动脉粥样硬化发展中的作用。与目的1相关的初步实验表明，高血糖L-FoxO 1小鼠具有高水平的血清甘油三酯、胆固醇和游离脂肪酸，并且从肝脏分泌极低密度脂蛋白的速率显著增加。研究FoxO 1对脂质代谢的影响机制对于实现本提案的目标是必要的，并将使我们能够重新审视胰岛素抵抗、高血糖和动脉粥样硬化之间的复杂关系。 公共卫生相关性：心血管疾病仍然是美国人口死亡的主要原因。动脉粥样硬化和冠状动脉疾病与糖尿病密切相关，但这些疾病之间的联系仍不清楚。确定这种关系中的关键参与者，包括FoxO 1基因等遗传效应子，以及高血糖和胰岛素抵抗等代谢参数，将提高我们对这些疾病的理解，以及如何更有效地治疗患者。

DESCRIPTION (provided by applicant): Dyslipidemia, including excess production and secretion of triglycerides and cholesterol by the liver, is a prominent metabolic abnormality of type 2 diabetes that can lead to the development of atherosclerosis and coronary artery disease. The relative roles of insulin resistance and hyperglycemia in the pathophysiology of this process are unclear, as are the cellular events that lead to dyslipidemia. Recently it has come to light that the transcription factor FoxO1 is an important effector in the pathway linking insulin signaling to lipoprotein turnover, in addition to its established role in regulating glucose production. Because FoxO1 can be regulated by both insulin (through phosphorylation-dependent inactivation) and glucose (through deacetylation- dependent activation), we reasoned that abnormalities of FoxO1 function might provide a unifying mechanism for the dyslipidemia of diabetes. To characterize FoxO1's contribution to lipoprotein metabolism, we will analyze lipid and cholesterol metabolism in liver-specific FoxO1 knockout mice (L-FoxO1) in two different conditions of metabolic stress: In Aim 1, mice will be rendered diabetic with streptozotocin (STZ), allowing us to examine the role of FoxO1 during hyperglycemia. In Aim 2, L-FoxO1 and controls will be bred onto an atherosclerosis- prone strain background (LDLR-/-) and fed a high fat, high cholesterol diet, wherein the role of FoxO1 in the development of atherosclerosis can be determined. Preliminary experiments relevant to Aim 1 demonstrated that hyperglycemic L-FoxO1 mice had high levels of serum triglycerides, cholesterol, and free fatty acids, and the rate of secretion of very low density lipoprotein from the liver was significantly increased. Investigation into the mechanism of FoxO1's effect on lipid metabolism is necessary to achieve the goals of this proposal, and will allow us to reexamine the complex relationship between insulin resistance, hyperglycemia and atherosclerosis. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases remain the leading cause of death in the US population. Atherosclerosis and coronary artery disease are tightly linked to diabetes, but the connection between these diseases remains unclear. Identifying the key players in this relationship, including genetic effectors such as the FoxO1 gene, and metabolic parameters such as hyperglycemia and insulin resistance, will improve our understanding of these diseases and how to treat patients more effectively.