Ceramide and cardiovascular risk in obesity

描述（由申请人提供）：肥胖在西方社会正达到流行病的比例，超过65%的美国成年人口超重或肥胖，并可能在未来几年内遭受临床心血管并发症。为了开发合理的治疗方法来治疗肥胖引起的心血管疾病，我们需要首先全面了解肥胖相关心血管风险的分子机制。最近的研究已经证明了脂质第二信使神经酰胺在包括肥胖、糖尿病和动脉粥样硬化在内的各种疾病中的重要性。该提案的总体目标是使用促血栓形成心血管风险基因纤溶酶原激活物抑制剂-1（PA 1 - 1）作为读出，以评估神经酰胺在与肥胖相关的心血管风险中所起的作用。在目标1中，我们将首先检验以下假设：在肥胖症的脂肪组织中神经酰胺本身的水平升高，并且与肥胖症相关的高胰岛素血症和升高的TNF-α有助于这种增加。在目的2中，我们将使用PA 1 -1作为读出来检验以下假设：神经酰胺和/或其生物活性代谢物鞘氨醇和鞘氨醇-1-磷酸是肥胖症心血管风险的重要调节剂，并且该途径还有助于胰岛素和TNF-α介导的PA 1 -1的肥胖相关增加。我们还将确定脂肪细胞中神经酰胺与PAI-1表达之间的信号传导机制。最后，在目标3中，我们将检验以下假设：脂肪组织/脂肪细胞中的膜结合TNF-α是肥胖症中神经酰胺和PA 1 -1增加的重要介质。这些研究不仅将促进我们对PAl-1诱导的分子机制的理解，PAl-1是一种在肥胖症中持续上调并与心血管风险正相关的基因，而且将具有临床意义，因为它们可以直接识别将肥胖症与心血管风险增加联系起来的新途径。

DESCRIPTION (provided by applicant): Obesity is reaching epidemic proportions in western societies and over 65% of the adult U.S. population is either overweight or obese and will likely suffer clinical cardiovascular complications in the years ahead. In order to develop rational therapeutic approaches to treat the cardiovascular conditions attributable to obesity we need to first develop a comprehensive understanding of the molecular mechanisms of obesity-associated cardiovascular risk. Recent studies have documented the importance of the lipid second messenger, ceramide, in a variety of disorders including obesity, diabetes and atherosclerosis. The overall goal of this proposal is to use the pro-thrombotic cardiovascular risk gene, plasminogen activator inhibitor-1 (PAl-l), as a read out, to evaluate the role played by ceramide in the cardiovascular risk associated with obesity. In Aim 1 we will initially test the hypothesis that the levels of ceramide itself are elevated in adipose tissues in obesity, and that the hyperinsulinemia and elevated TNF-alpha associated with obesity contribute to this increase. In Aim 2, we will use PAl-1 as a read-out to test the hypothesis that ceramide and/or its bioactive metabolites, sphingosine and sphingosine-l-phosphate, are important regulators of cardiovascular risk in obesity, and that this pathway also contributes to obesity-associated increase in PAl-1 mediated by insulin and TNF-alpha. We also will determine signaling mechanisms that link ceramide to PAl-1 expression in the adipocyte. Finally, in Aim 3, we will test the hypothesis that membrane-bound TNF-alpha in the adipose tissue/adipocytes is an important mediator of increased ceramide and PAl-1 in obesity. These studies will not only advance our understanding of the molecular mechanisms that contribute to the induction of PAl-l, a gene that is consistently up regulated in obesity and positively correlated with cardiovascular risk, but will be clinically significant as they may directly identify novel pathways that link obesity to increased cardiovascular risk.