Regulation of Cholesterol Homeostasis by a Novel Long Non-coding RNA LASER
Regulation of Cholesterol Homeostasis by a Novel Long Non-coding RNA LASER
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新型长非编码 RNA 激光器调节胆固醇稳态
DOI：
10.1038/s41598-019-44195-2
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发表时间：
2019-05-22
影响因子：
4.6
通讯作者：
Zeng, Chunyu
中科院分区：
文献类型：
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作者：
Li, Chuanwei;Hu, Zhangxue;Zeng, Chunyu
全基因组关联研究（GWAS）已经确定了许多与脂质代谢相关的基因的遗传变异。然而，这些变化是如何影响脂质水平的仍然是难以捉摸的。长链非编码rna （lncRNAs）参与了多种生物过程。我们假设lncrna可能位于疾病或性状相关的DNA区域，以调节脂质代谢。本研究的目的是研究脂质相关DNA区域的lncrna是否以及如何调节肝细胞中的胆固醇稳态。本研究通过生物信息学分析，在脂质相关单核苷酸多态性基因区（LASER）鉴定出一个新的长链非编码RNA。我们报道LASER在肝细胞和外周单核细胞（PBMCs）中高度表达。临床研究表明，LASER表达与含胆固醇载脂蛋白水平呈正相关。特别是，我们发现LASER与无他汀类药物患者血浆PCSK9水平呈正相关。sirna介导的LASER基因敲低可显著降低细胞内胆固醇水平，影响胆固醇代谢相关基因的表达。转录组分析表明，LASER基因的敲低会影响代谢途径相关基因的表达。我们发现，激光敲除后，HNF-1α和PCSK9减少。有趣的是，PCSK9的减少可以通过小檗碱（一种天然降胆固醇化合物，具有HNF-1α拮抗剂的作用）的治疗而被阻断。在机制上，我们发现LASER在细胞核中与CoREST/REST复合体的成员LSD1（赖氨酸特异性去甲基酶1）结合。激光敲除增强LSD1靶向基因组位点，导致HNF-1α基因启动子区域组蛋白H3赖氨酸4单甲基化降低。相反，LSD1敲除消除了LASER对HNF-1α和PCSK9表达的影响。最后，我们发现他汀类药物治疗增加了LASER表达，同时增加了PCSK9表达，提示胆固醇对LASER表达的反馈调节。这一观察结果可以部分解释他汀类药物在抗胆固醇治疗期间的逃逸。这些发现确定了一种新的lncRNA在胆固醇稳态中的作用。治疗靶向激光可能是临床上增强他汀类药物对胆固醇水平影响的有效方法。
Genome-wide association studies (GWAS) have identified many genetic variants in genes related to lipid metabolism. However, how these variations affect lipid levels remains elusive. Long non-coding RNAs (lncRNAs) have been implicated in a variety of biological processes. We hypothesize lncRNAs are likely to be located within disease or trait-associated DNA regions to regulate lipid metabolism. The aim of this study was to investigate whether and how lncRNAs in lipid- associated DNA regions regulate cholesterol homeostasis in hepatocytes. In this study, we identified a novel long non-coding RNA in Lipid Associated Single nucleotide polymorphism gEne Region (LASER) by bioinformatic analysis. We report that LASER is highly expressed in both hepatocytes and peripheral mononuclear cells (PBMCs). Clinical studies showed that LASER expression is positively related with that of cholesterol containing apolipoprotein levels. In particular, we found that LASER is positively correlated with plasma PCSK9 levels in statin free patients. siRNAs mediated knock down of LASER dramatically reduces intracellular cholesterol levels and affects the expression of genes involved in cholesterol metabolism. Transcriptome analyses show that knockdown of LASER affects the expression of genes involved in metabolism pathways. We found that HNF-1α and PCSK9 were reduced after LASER knock-down. Interestingly, the reduction of PCSK9 can be blocked by the treatment of berberine, a natural cholesterol-lowering compound which functions as a HNF-1α antagonist. Mechanistically, we found that LASER binds to LSD1 (lysine-specific demethylase 1), a member of CoREST/REST complex, in nucleus. LASER knock-down enhance LSD1 targeting to genomic loci, resulting in decreased histone H3 lysine 4 mono-methylation at the promoter regions of HNF-1α gene. Conversely, LSD1 knock-down abolished the effect of LASER on HNF-1α and PCSK9 expressions. Finally, we found that statin treatment increased LASER expression, accompanied with increased PCSK9 expression, suggesting a feedback regulation of cholesterol on LASER expression. This observation may partly explain the statin escape during anti-cholesterol treatment. These findings identified a novel lncRNA in cholesterol homeostasis. Therapeutic targeting LASER might be an effective approach to augment the effect of statins on cholesterol levels in clinics.