Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic beta-cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, beta-cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.

中文翻译：

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鞘脂、胰岛素抵抗和代谢疾病：体内操纵鞘脂代谢的新见解。

肥胖和血脂异常是代谢紊乱的危险因素，包括糖尿病和心血管疾病。神经酰胺和葡萄糖神经酰胺等鞘脂虽然在大多数组织中是脂质环境中相对较少的成分，但在与过度肥胖相关的后遗症发作时可能是致病性最强的脂质之一。与肥胖相关的循环因子（例如饱和脂肪酸、炎性细胞因子）选择性地诱导促进鞘脂合成的酶，脂质组学分析揭示了组织鞘脂水平与某些代谢疾病之间的关系。此外，对培养细胞和分离组织的研究表明，鞘脂与某些与糖尿病和心血管疾病相关的细胞事件有关，包括胰岛素抵抗、胰腺 β 细胞衰竭、心肌病、和血管功能障碍。然而，关于鞘脂导致胰岛素抵抗、糖尿病和动脉粥样硬化的确切证据直到最近才出现，因为研究人员发现，控制啮齿动物鞘脂合成的酶的药理学抑制或基因消融可以改善这些病症中的每一种。在此，我们将回顾神经酰胺和其他鞘脂代谢物在胰岛素抵抗、β 细胞衰竭、心肌病和血管功能障碍中的作用，重点关注这些体内研究，这些研究将控制鞘脂代谢的酶确定为对抗代谢疾病的治疗靶点。研究人员发现，控制啮齿类动物鞘脂合成的酶的药理学抑制或遗传消融可以改善上述每一种情况。在此，我们将回顾神经酰胺和其他鞘脂代谢物在胰岛素抵抗、β 细胞衰竭、心肌病和血管功能障碍中的作用，重点关注这些体内研究，这些研究将控制鞘脂代谢的酶确定为对抗代谢疾病的治疗靶点。研究人员发现，控制啮齿类动物鞘脂合成的酶的药理学抑制或遗传消融可以改善上述每一种情况。在此，我们将回顾神经酰胺和其他鞘脂代谢物在胰岛素抵抗、β 细胞衰竭、心肌病和血管功能障碍中的作用，重点关注这些体内研究，这些研究将控制鞘脂代谢的酶确定为对抗代谢疾病的治疗靶点。