CELLULAR MECHANISMS THAT PROMOTE OR PREVENT LIPOTOXICITY

描述（由申请方提供）：非脂肪组织中的过量脂质蓄积与细胞功能障碍和细胞死亡相关，可能导致糖尿病和肥胖症中胰岛素抵抗、非酒精性脂肪性肝炎和心肌病的发病机制。在这些病理生理反应中涉及的机制已在培养细胞中通过补充具有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涉及氧化和内质网应激的机制导致培养细胞的凋亡。这项建议将测试的假设，即细胞与基因中断，防止脂毒性细胞死亡可能有缺陷的脂肪酸进口，脂肪酸通道，脂质诱导的氧化应激，或在响应内质网结构和功能的扰动。我们的前两个目标将采用生物化学和遗传学的方法在培养的细胞，以确定分子靶点和信号通路的脂毒性反应。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相关。这些研究的结果将为糖尿病和肥胖症患者非脂肪组织中过量脂质积聚的脂毒性反应提供新的见解。公共卫生相关性：心力衰竭是肥胖症和糖尿病的严重并发症，与心脏脂肪代谢的改变有关。本申请中提出的研究将表征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症的转基因小鼠模型，以了解这些机制如何影响心肌功能。鉴于糖尿病和肥胖患者心力衰竭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.