Control of lipid metabolism in insulin resistant states

描述（由申请人提供）：代谢综合征是一种胰岛素抵抗状态，其特征为脂质稳态的多种紊乱，导致血脂异常、动脉粥样硬化、肝脂肪变性和胆固醇结石。驱动这些紊乱的因素是未知的，但必须确定，以有效地治疗代谢综合征。转录因子FoxO 1和固醇调节元件结合蛋白（SREBP）-1c是胰岛素作用的关键调节因子。FoxO 1不仅促进促血管生成酶的转录，而且促进VLDL分泌和胆汁胆固醇分泌所必需的酶的转录。另一方面，SREBP-1c诱导脂肪生成酶。在正常肝脏中，胰岛素抑制FoxO 1并激活SREBP-1c。在代谢综合征中，胰岛素不能抑制FoxO 1，但SREBP-1c却矛盾地增加。这就提出了一个问题，在胰岛素抵抗的情况下，是什么驱动SREBP-1c？我们的初步数据显示，对胰岛素无反应的肝胰岛素受体敲除（LIRKO）小鼠的肝脏显示响应于饮食碳水化合物的SREBP-1c的雷帕霉素敏感性增加。这些数据表明存在胰岛素非依赖性信号通路，即使在存在胰岛素抵抗的情况下，也可能允许过量摄入碳水化合物来激活SREBP-1c和脂肪生成。该提案的首要目标是确定胰岛素抵抗状态下脂质代谢的关键驱动因素。我们假设FoxO 1不能被胰岛素抑制，导致血脂异常、动脉粥样硬化和胆结石;而SREBP-1c由营养素诱导，导致脂肪生成和脂肪变性。我们的目的是（1）确定FoxO 1和SREBP-1c通过敲低FoxO 1或重建LIRKO小鼠肝脏中SREBP-1c表达促进动脉粥样硬化、脂肪变性和胆固醇结石的程度;（2）确定营养素激活SREBP-1c和脂肪生成的胰岛素非依赖性信号通路。我们期望发现FoxO 1和SREBP-1c定义了两个不同的代谢信号通路，这两个通路对于代谢综合征中存在的紊乱的完整补充都是必要的。

DESCRIPTION (provided by applicant): The metabolic syndrome is a state of insulin resistance characterized by multiple derangements in lipid homeostasis, leading to dyslipidemia, atherosclerosis, hepatic steatosis, and cholesterol gallstones. The factors that drive these derangements are unknown but must be determined in order to effectively treat the metabolic syndrome. The transcription factors FoxO1 and Sterol Regulatory Element Binding Protein (SREBP)-1c are key regulators of insulin action. FoxO1 promotes transcription of the gluconeogenic enzymes, but also the enzymes necessary for VLDL secretion and biliary cholesterol secretion. SREBP-1c, on the other hand, induces the lipogenic enzymes. In normal livers, insulin suppresses FoxO1 and activates SREBP-1c. In the metabolic syndrome, insulin fails to suppress FoxO1 but SREBP-1c is paradoxically increased. This raises the question, what drives SREBP-1c in the presence of insulin resistance? Our preliminary data show that the livers of Liver Insulin Receptor Knockout (LIRKO) mice, which are unresponsive to insulin, show a rapamycin- sensitive increase in SREBP-1c in response to dietary carbohydrates. These data indicate the existence of an insulin-independent signaling pathway that could potentially allow the excessive consumption of carbohydrates to activate SREBP-1c and lipogenesis, even in the presence of insulin resistance. The overarching goal of this proposal is to identify the key driver of lipid metabolism in the insulin resistant state. We hypothesize that FoxO1, which fails to be suppressed by insulin, drives dyslipidemia, atherosclerosis and gallstones; but that SREBP-1c, induced by nutrients, drives lipogenesis and steatosis. Our aims are to (1) determine the extent to which FoxO1 and SREBP-1c promote atherosclerosis, steatosis, and cholesterol gallstones by knocking down FoxO1 or reconstituting SREBP-1c expression in the livers of LIRKO mice; and (2) to define the insulin-independent signaling pathways by which nutrients can activate SREBP-1c and lipogenesis. We expect to find that FoxO1 and SREBP-1c define two distinct metabolic signaling pathways that are both necessary for the full complement of derangements present in the metabolic syndrome.