Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity
Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity
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DOI：
10.1074/jbc.m115.680199
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发表时间：
2015-12-04
影响因子：
4.8
通讯作者：
Dixit, Vishwa Deep
中科院分区：
文献类型：
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作者：
Camell, Christina D.;Nguyen, Kim Y.;Dixit, Vishwa Deep
肥胖期间饮食中的脂质过载和卡路里过量是一种低级别的慢性炎症状态，其适当代谢葡萄糖或脂肪的能力减弱。巨噬细胞在维持脂肪组织动态平衡方面起关键作用，部分是通过调节脂肪代谢、能量动态平衡和组织重塑。在高脂饮食诱导的肥胖过程中，巨噬细胞被神经酰胺和棕榈酸酯等脂类衍生的危险信号激活，并以Nlrp3依赖的方式促进脂肪组织的炎症。鉴于脂肪酸在巨噬细胞中的代谢命运尚不完全清楚，我们假设巨噬细胞中通过限速酶丝氨酸棕榈酰转移酶长链(Sptlc)-2从头合成神经酰胺是饱和脂肪酸驱动的Nlrp3炎症体激活所必需的。在这里，我们报道了线粒体靶向过表达过氧化氢酶，它是为了减轻氧化应激，控制神经酰胺诱导的Nlrp3炎症体激活，但不影响ATP介导的caspase-1裂解。令人惊讶的是，髓系细胞特异性Sptlc2的缺失并不是棕榈酸酯驱动的Nlrp3炎症体激活所必需的。此外，去除巨噬细胞中的Sptlc2并不影响巨噬细胞极化或肥胖诱导的脂肪组织白细胞增多。与这些数据一致的是，使用高胰岛素-正常血糖钳夹研究胰岛素抵抗发现，在缺乏巨噬细胞神经酰胺从头合成机制的肥胖小鼠中没有显著差异。这些数据表明，交替的代谢途径控制着巨噬细胞中脂肪酸衍生神经酰胺的合成和肥胖时Nlrp3炎症体的激活。
Dietary lipid overload and calorie excess during obesity is a low grade chronic inflammatory state with diminished ability to appropriately metabolize glucose or lipids. Macrophages are critical in maintaining adipose tissue homeostasis, in part by regulating lipid metabolism, energy homeostasis, and tissue remodeling. During high fat diet-induced obesity, macrophages are activated by lipid derived "danger signals" such as ceramides and palmitate and promote the adipose tissue inflammation in an Nlrp3 inflammasome-dependent manner. Given that the metabolic fate of fatty acids in macrophages is not entirely elucidated, we have hypothesized that de novo synthesis of ceramide, through the rate-limiting enzyme serine palmitoyltransferase long chain (Sptlc)-2, is required for saturated fatty acid-driven Nlrp3 inflammasome activation in macrophages. Here we report that mitochondrial targeted overexpression of catalase, which is established to mitigate oxidative stress, controls ceramide-induced Nlrp3 inflammasome activation but does not affect the ATP-mediated caspase-1 cleavage. Surprisingly, myeloid cell-specific deletion of Sptlc2 is not required for palmitate-driven Nlrp3 inflammasome activation. Furthermore, the ablation of Sptlc2 in macrophages did not impact macrophage polarization or obesity-induced adipose tissue leukocytosis. Consistent with these data, investigation of insulin resistance using hyperinsulinemic-euglycemic clamps revealed no significant differences in obese mice lacking ceramide de novo synthesis machinery in macrophages. These data suggest that alternate metabolic pathways control fatty acid-derived ceramide synthesis in macrophage and the Nlrp3 inflammasome activation in obesity.