SREBP2 内含子来源的 miR-33 抑制胆固醇外排和脂肪酸氧化。

Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation.

机构信息

Laboratory for Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.

出版信息

J Biol Chem. 2010 Oct 29;285(44):33652-61. doi: 10.1074/jbc.M110.152090. Epub 2010 Aug 22.

Abstract

The regulation of synthesis, degradation, and distribution of lipids is crucial for homeostasis of organisms and cells. The sterol regulatory element-binding protein (SREBP) transcription factor family is post-translationally activated in situations of reduced lipid abundance and activates numerous genes involved in cholesterol, fatty acid, and phospholipid synthesis. In this study, we provide evidence that the primary transcript of SREBP2 contains an intronic miRNA (miR-33) that reduces cellular cholesterol export via inhibition of translation of the cholesterol export pump ABCA1. Notably, miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation. The genetic locus encoding SREBP2 and miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids. These results add an additional layer of complexity to our understanding of lipid homeostasis and might open possibilities for future therapeutic intervention.

摘要

脂质的合成、降解和分布的调节对于生物体和细胞的内稳态至关重要。固醇调节元件结合蛋白(SREBP)转录因子家族在脂质含量减少的情况下被翻译后激活,并激活许多参与胆固醇、脂肪酸和磷脂合成的基因。在这项研究中,我们提供了证据表明,SREBP2 的初级转录本含有一个内含子 miRNA(miR-33),通过抑制胆固醇外排泵 ABCA1 的翻译来减少细胞内胆固醇的外排。值得注意的是,miR-33 还抑制了编码脂肪酸β-氧化的几种蛋白的翻译,包括 CPT1A、HADHB 和 CROT,从而减少脂肪酸的降解。因此,编码 SREBP2 和 miR-33 的基因座包含一种蛋白,该蛋白增加脂质合成,而一种 miRNA 则防止新合成脂质的外排和降解。这些结果为我们理解脂质内稳态增加了一个新的复杂性层面,并可能为未来的治疗干预提供了可能性。

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