NAD+-dependent Sirtuin 1 and 6 Proteins Coordinate a Switch from Glucose to Fatty Acid Oxidation during the Acute Inflammatory Response
NAD+-dependent Sirtuin 1 and 6 Proteins Coordinate a Switch from Glucose to Fatty Acid Oxidation during the Acute Inflammatory Response
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DOI：
10.1074/jbc.m112.362343
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发表时间：
2012-07-27
影响因子：
4.8
通讯作者：
McCall, Charles E.
中科院分区：
文献类型：
--
作者：
Liu, Tie Fu;Vachharajani, Vidula T.;McCall, Charles E.
急性炎症的早期阶段是合成代谢阶段，主要需要糖酵解，线粒体葡萄糖氧化减少以获得能量，而后期适应阶段是分解代谢阶段，主要需要脂肪酸氧化以获得能量。我们以前报道过，TLR4刺激后急性炎症反应从早期到晚期的转换依赖于脱乙酰酶sirtuin 1(SirT1)的NAD(+)激活。在这里，我们测试了sirtuins对NAD(+)的感知是否将代谢极性与急性炎症反应结合在一起。我们发现，在TLR4刺激的THP-1前单核细胞中，随着早期炎症转化为晚期炎症，SirT1和Sirt6支持从糖酵解增加到脂肪酸氧化增加的转换。糖酵解的增强需要低氧诱导因子-1α上调葡萄糖转运蛋白Glut1、磷酸果糖激酶和丙酮酸脱氢酶激酶1，从而阻断丙酮酸脱氢酶并减少线粒体葡萄糖的氧化。转变为晚期急性炎症和脂肪酸氧化增加需要过氧化物酶体增殖物激活受体γ共激活剂PGC-1α和β来增加外膜CD36和脂肪酸线粒体转运体肉碱棕榈酰转移酶1。早期和晚期反应之间的代谢耦合还需要烟酰胺磷酸转移酶(NAMPT)产生NAD(+)，激活SIRT6以减少糖酵解，激活SirT1以增加脂肪氧化。我们证实了人败血症血白细胞和小鼠脓毒症脾细胞在免疫抑制后期代谢极性的相似变化。我们得出结论，依赖NAD(+)的生物能量转移将代谢与急性炎症的早期和晚期联系起来。
The early initiation phase of acute inflammation is anabolic and primarily requires glycolysis with reduced mitochondrial glucose oxidation for energy, whereas the later adaptation phase is catabolic and primarily requires fatty acid oxidation for energy. We reported previously that switching from the early to the late acute inflammatory response following TLR4 stimulation depends on NAD(+) activation of deacetylase sirtuin 1 (SirT1). Here, we tested whether NAD(+) sensing by sirtuins couples metabolic polarity with the acute inflammatory response. We found in TLR4-stimulated THP-1 promonocytes that SirT1 and SirT 6 support a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. Glycolysis enhancement required hypoxia-inducing factor-1 alpha to up-regulate glucose transporter Glut1, phospho-fructose kinase, and pyruvate dehydrogenase kinase 1, which interrupted pyruvate dehydrogenase and reduced mitochondrial glucose oxidation. The shift to late acute inflammation and elevated fatty acid oxidation required peroxisome proliferator-activated receptor gamma coactivators PGC-1 alpha and beta to increase external membrane CD36 and fatty acid mitochondrial transporter carnitine palmitoyl transferase 1. Metabolic coupling between early and late responses also required NAD(+) production from nicotinamide phosphoryltransferase (Nampt) and activation of SirT6 to reduce glycolysis and SirT1 to increase fatty oxidation. We confirmed similar shifts in metabolic polarity during the late immuno-suppressed stage of human sepsis blood leukocytes and murine sepsis splenocytes. We conclude that NAD(+)-dependent bioenergy shifts link metabolism with the early and late stages of acute inflammation.