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Regulation of ABCG4 transporter expression by sterols and LXR ligands
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-10-22 , DOI: 10.1016/j.bbagen.2020.129769
Alryel Yang 1 , Amjad Z Alrosan 1 , Laura J Sharpe 2 , Andrew J Brown 2 , Richard Callaghan 3 , Ingrid C Gelissen 1
Affiliation  

Background

Oxysterols, which are derivatives of cholesterol produced by enzymic or non-enzymic pathways, are potent regulators of cellular lipid homeostasis. Sterol homeostasis in the brain is an important area of interest with regards to neurodegenerative conditions like Alzheimer's disease (AD). Brain cells including neurons and astrocytes express sterol transporters belonging to the ABC transporter family of proteins, including ABCA1, ABCG1 and ABCG4, and these transporters are considered of interest as therapeutic targets. Although regulation of ABCA1 and ABCG1 is well established, regulation of ABCG4 is still controversial, in particular whether the transporter is an Liver X receptor (LXR) target. ABCG4 is thought to transport cholesterol, oxysterols and cholesterol synthesis intermediates, and was recently found on the blood brain barrier (BBB), implicated in amyloid-beta export. In this study, we investigate the regulation of ABCG4 by oxysterols, cholesterol-synthesis intermediates and cholesterol itself.

Methods

ABC transporter expression was measured in neuroblastoma and gliablastoma cell lines and cells overexpressing ABCG4 in response to synthetic LXR ligands, oxysterols and cholesterol-synthesis intermediates.

Results

In contrast to previous reports, ABCG4 expression was induced by a synthetic LXR ligand in U87-MG astrocytes but not in neuroblastoma and BBB endothelial cell lines. In addition, ABCG4 protein was stabilized by cholesterol as was previously shown for ABCG1. ABCG4 protein was furthermore stabilized by cholesterol-synthesis intermediates, desmosterol, lathosterol and lanosterol.

Conclusions

These results identify new aspects of the post-translational control of ABCG4 that warrant further exploration into the role of this transporter in the maintenance of sterol homeostasis in the brain.



中文翻译:

甾醇和 LXR 配体对 ABCG4 转运蛋白表达的调节

背景

氧化甾醇是由酶或非酶途径产生的胆固醇衍生物,是细胞脂质稳态的有效调节剂。大脑中的甾醇稳态是与阿尔茨海默病 (AD) 等神经退行性疾病相关的一个重要领域。包括神经元和星形胶质细胞在内的脑细胞表达属于 ABC 转运蛋白家族的甾醇转运蛋白,包括 ABCA1、ABCG1 和 ABCG4,这些转运蛋白被认为是治疗靶点。尽管 ABCA1 和 ABCG1 的调节已经确立,但 ABCG4 的调节仍然存在争议,特别是转运蛋白是否是肝脏 X 受体 (LXR) 的靶标。ABCG4 被认为是运输胆固醇、氧甾醇和胆固醇合成中间体,最近在血脑屏障 (BBB) 上被发现,与β-淀粉样蛋白输出有关。在这项研究中,我们研究了氧甾醇、胆固醇合成中间体和胆固醇本身对 ABCG4 的调节作用。

方法

在神经母细胞瘤和胶质母细胞瘤细胞系以及响应合成 LXR 配体、氧甾醇和胆固醇合成中间体过表达 ABCG4 的细胞中测量 ABC 转运蛋白表达。

结果

与以前的报道相反,ABCG4 表达是由 U87-MG 星形胶质细胞中的合成 LXR 配体诱导的,但在神经母细胞瘤和 BBB 内皮细胞系中没有。此外,如先前对 ABCG1 所示,ABCG4 蛋白被胆固醇稳定。此外,ABCG4 蛋白还通过胆固醇合成中间体、去甾醇、乳甾醇和羊毛甾醇来稳定。

结论

这些结果确定了 ABCG4 翻译后控制的新方面,值得进一步探索这种转运蛋白在维持大脑中甾醇稳态中的作用。

更新日期:2020-11-02
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