Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.
Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.
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DOI：
10.3410/f.726427886.793521202
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
T. Sallam;Marius C. Jones;T. Gilliland;Li Zhang;Xiaohui Wu;Ascia;Eskin;J. Sandhu;D. Casero-D.-Cas
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文献类型：
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作者：
T. Sallam;Marius C. Jones;T. Gilliland;Li Zhang;Xiaohui Wu;Ascia;Eskin;J. Sandhu;D. Casero-D.-Cas
肝脏X受体（LXRs）是细胞和系统胆固醇稳态的转录调节因子。在胆固醇过量的情况下，LXR激活诱导参与胆固醇流出的一系列基因的表达1，通过促进脂肪酸合成2促进胆固醇酯化，并通过低密度脂蛋白受体（LDLR）3抑制胆固醇摄取。甾醇含量在大多数细胞类型和整个生物体中保持在一个狭窄的范围内的事实表明，调节途径之间必须存在广泛的串扰。然而，整合LXR与其他脂质代谢途径的分子机制尚未完全了解。在这里，我们表明，配体激活LXR在肝脏不仅促进胆固醇流出，但同时也抑制胆固醇的生物合成。我们进一步确定了长的非编码RNA LeXis作为这种效应的一种介质。肝脏LeXis表达的研究是通过小鼠实验和数据分析进行的。参与小鼠实验和数据分析。进行了RNA-seq实验，并验证了LeXis作为LXR靶标。处理和分析下一代测序数据。MCJ进行并分析了RACE实验。JW进行了质谱分析。MK和RL提供并独立验证了靶向LeXis的ASO。TS和PT手稿。TS、MCJ和PT根据所有作者的意见编辑了手稿。所有人都讨论了结果，并批准了手稿的最终版本。非编码LeX是LXR信号传导对肝脏脂质代谢的复杂作用的额外介质。LeX是LXR抑制胆固醇合成的能力。对于表达分析，使用PCR Applied Biosystems Applied Biosystems Quant Studio 6 Flex。将结果归一化为亲环蛋白。石蜡包埋肝脏的免疫组织化学染色由转化病理学核心实验室完成。
The liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. In the setting of cholesterol excess, LXR activation induces the expression of a battery of genes involved in cholesterol efflux 1 , facilities cholesterol esterification by promoting fatty acid synthesis 2 , and inhibits cholesterol uptake by the low-density lipoprotein receptor (LDLR) 3 . The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways, are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as one mediator of this effect. Hepatic LeXis expression is the study performed the majority of mouse experiments and data analysis. participated in mouse experiments and data analysis. performed RNA-seq experiments and validated LeXis as an LXR target. and processed and analyzed next-generation sequencing data. MCJ performed and analyzed the RACE experiments. JW performed the Mass Spectrometry Analysis. MK and RL provided and independently validated ASOs targeting LeXis. TS and PT the manuscript. TS, MCJ and PT edited the manuscript with input from all authors. All discussed the results and approved the final version of the manuscript. non-coding LeXis additional mediator of the complex effects of LXR signaling on hepatic lipid metabolism. LeXis the ability of LXRs inhibit cholesterol synthesis. involvement additional pathways in this crosstalk resulting tested For expression analysis, using PCR Applied Biosystems Applied Biosystems Quant Studio 6 Flex. Results are normalized to cyclophilin. Immunohistochemical staining of paraffin-embedded livers were done by Translational Pathology Core Laboratory.