Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia.
Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia.
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DOI：
10.1016/j.molimm.2009.08.023
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发表时间：
2009-12
影响因子：
3.6
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Maitra U;Chang S;Singh N;Li L
尽管脓毒症和内毒素血症期间均发生炎症和代谢并发症，但相对较少的研究探讨了脓毒症期间lps调节代谢变化的分子机制。在本报告中，我们证明了LPS抑制游离脂肪酸（FFA）氧化，从而导致血浆中FFA和甘油三酯（TG）水平升高。此外，这一过程依赖于白细胞介素-1受体相关激酶1 (IRAK-1)，这是TLR4细胞内关键信号激酶之一。与野生型（WT）小鼠相比，注射致死LPS后，IRAK-1−/−小鼠血浆FFA和TG水平没有显著升高。在机制上，我们证明了LPS通过降低WT而不是IRAK-1 - / -小鼠肝脏和肾脏组织中关键FFA氧化基因（包括CPT-1和MCAD）的表达水平来抑制FFA氧化。CPT-1和MCAD的表达受核受体和共受体包括PPARα和PGC-1α的控制。我们观察到LPS选择性地抑制WT组织中PPARα和PGC-1α的水平，但不抑制IRAK-1 - / -小鼠。因此，IRAK-1−/−小鼠在LPS致死剂量后具有更高的存活率。我们目前的研究揭示了IRAK-1在LPS诱导的代谢改变中的新作用。
Although both inflammatory and metabolic complications occur during sepsis and endotoxemia, relatively few studies have examined the molecular mechanism underlying LPS-modulated metabolic changes during sepsis. In this report, we have demonstrated that LPS suppresses free fatty acid (FFA) oxidation, and consequently contributes to elevated plasma levels of FFA and triglyceride (TG). Furthermore, this process depends upon the interleukin-1 receptor associated kinase 1 (IRAK-1), one of the key TLR4 intracellular signaling kinases. IRAK-1−/− mice fail to exhibit the dramatic rise in plasma FFA and TG levels compared to wild type (WT) mice following lethal LPS injection. Mechanistically, we demonstrated that LPS suppresses FFA oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues of WT but not IRAK-1−/− mice. The expression of CPT-1 and MCAD is controlled by nuclear receptors and co-receptors including PPARα and PGC-1α. We observed that LPS selectively suppresses the levels of PPARα and PGC-1α in tissues from WT, but not IRAK-1−/− mice. Consequently, IRAK-1−/− mice have a higher survival rate following a lethal dose of LPS. Our current study reveals a novel role for IRAK-1 in the metabolic alterations induced by LPS.
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影响因子：
6.5
作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2004.05.035
发表时间：
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