Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression
Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression
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DOI：
10.1242/jcs.106682
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发表时间：
2012-07-15
影响因子：
4
通讯作者：
Simos, George
中科院分区：
文献类型：
--
作者：
Mylonis, Ilias;Sembongi, Hiroshi;Simos, George
低氧适应涉及低氧诱导转录因子（HIF），需要细胞代谢的重编程，这在生理和病理过程中都是必不可少的。与HIF-1在葡萄糖代谢中的既定作用相反，HIF的参与和缺氧对脂质代谢影响的分子机制的特征很差。在这里，我们报告说，人体细胞暴露于缺氧导致甘油三酯和脂滴的积累。这伴随着脂蛋白1的诱导，脂蛋白1是催化甘油三酯生物合成中倒数第二步的磷脂酸磷酸酶同种型，而脂蛋白2不受影响。脂蛋白1表达的低氧上调主要涉及HIF-1，其结合脂蛋白1基因启动子中的单个远端低氧应答元件并导致其在低氧条件下活化。缺氧甘油三酯或脂滴的积累可以通过siRNA介导的脂蛋白1表达沉默或山奈酚介导的HIF-1抑制来阻断。我们的结论是，由HIF-1直接控制lipin 1的转录是一个重要的调节功能的脂质代谢和适应缺氧。
Adaptation to hypoxia involves hypoxia-inducible transcription factors (HIFs) and requires reprogramming of cellular metabolism that is essential during both physiological and pathological processes. In contrast to the established role of HIF-1 in glucose metabolism, the involvement of HIFs and the molecular mechanisms concerning the effects of hypoxia on lipid metabolism are poorly characterized. Here, we report that exposure of human cells to hypoxia causes accumulation of triglycerides and lipid droplets. This is accompanied by induction of lipin 1, a phosphatidate phosphatase isoform that catalyzes the penultimate step in triglyceride biosynthesis, whereas lipin 2 remains unaffected. Hypoxic upregulation of lipin 1 expression involves predominantly HIF-1, which binds to a single distal hypoxia-responsive element in the lipin 1 gene promoter and causes its activation under low oxygen conditions. Accumulation of hypoxic triglycerides or lipid droplets can be blocked by siRNA-mediated silencing of lipin 1 expression or kaempferol-mediated inhibition of HIF-1. We conclude that direct control of lipin 1 transcription by HIF-1 is an important regulatory feature of lipid metabolism and its adaptation to hypoxia.