CELLULAR MECHANISMS THAT PROMOTE OR PREVENT LIPOTOXICITY

描述（由申请人提供）：非脂肪组织中过量脂质积累与细胞功能障碍和细胞死亡相关，可能导致胰岛素抵抗、非酒精性脂肪性肝炎和糖尿病和肥胖症心肌病的发病机制。参与这些病理生理反应的机制已经在培养细胞中通过补充高浓度游离脂肪酸的生长培养基进行了研究。饱和脂肪酸棕榈酸酯通过氧化和内质网应激机制导致培养细胞凋亡。这一提议将验证这样一种假设，即具有阻止脂毒性细胞死亡的基因破坏的细胞可能在脂肪酸进口、脂肪酸通道、脂质诱导的氧化应激或内质网结构和功能扰动的反应中存在缺陷。我们的前两个目标将在培养细胞中使用生化和遗传方法来识别脂肪毒性反应的分子靶点和信号通路。在我们的第三个目标中，我们将把我们的发现转化为与糖尿病心血管疾病相关的小鼠模型，其中心肌细胞中的脂质积累与心力衰竭有关。这些研究结果将为糖尿病和肥胖症非脂肪组织中过量脂质积累的脂毒性反应提供新的见解。公共卫生相关性：心力衰竭是肥胖和糖尿病的一种严重的医学并发症，与心脏脂肪代谢的改变有关。本应用程序中提出的研究将描述过量脂肪如何导致细胞功能障碍和死亡，并将这些发现扩展到糖尿病和肥胖的转基因小鼠模型，以了解这些机制如何影响心肌功能。鉴于心力衰竭在糖尿病和肥胖患者中的患病率及其相关的发病率和死亡率，进一步了解这种疾病的过程将有助于开发新的治疗和预防策略。

DESCRIPTION (provided by applicant): Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that may contribute to the pathogenesis of insulin resistance, non-alcoholic steatohepatitis, and cardiomyopathy in diabetes and obesity. Mechanisms involved in these pathophysiological responses have been studied in cultured cells by supplementation of growth media with high concentrations of free fatty acids. The saturated fatty acid, palmitate, leads to apoptosis in cultured cells by a mechanism involving oxidative and endoplasmic reticulum stress. This proposal will test the hypothesis that cells with gene disruptions that prevent lipotoxic cell death may have defects in fatty acid import, in fatty acid channeling, in lipid-induced oxidative stress, or in the response to perturbations of endoplasmic reticulum structure and function. Our first two aims will employ biochemical and genetic approaches in cultured cells to identify molecular targets and signaling pathways in the lipotoxic response. In our third aim, we will translate our findings to mouse models relevant to diabetic cardiovascular disease, in which lipid accumulation in cardiomyocytes is associated with heart failure. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in non-adipose tissues in diabetes and obesity. PUBLIC HEALTH RELEVANCE: Heart failure is a serious medical complication of obesity and diabetes that is linked to alterations in fat metabolism in the heart. The studies proposed in this application will characterize how excess fat leads to dysfunction and death of cells and extend these findings to genetically modified mouse models of diabetes and obesity to understand how these mechanisms affect heart muscle function. Given the prevalence of heart failure in diabetic and obese patients and its associated morbidity and mortality, further understanding of this disease process will facilitate the development of new treatments and preventative strategies.