Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice.
Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice.
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小鼠肝脏RBFOX2通过Scarb1选择性剪接调节胆固醇稳态。
DOI：
10.1038/s42255-022-00681-y
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发表时间：
2022-12
影响因子：
20.8
通讯作者：
Vernia, Santiago
中科院分区：
文献类型：
--
作者：
Paterson, Helen A. B.;Yu, Sijia;Artigas, Natalia;Prado, Miguel A.;Haberman, Nejc;Wang, Yi-Fang;Jobbins, Andrew M.;Pahita, Elena;Mokochinski, Joao;Hall, Zoe;Guerin, Maryse;Paulo, Joao A.;Ng, Soon Seng;Villarroya, Francesc;Rashid, Sheikh Tamir;Le Goff, Wilfried;Lenhard, Boris;Cebola, Ines;Finley, Daniel;Gygi, Steven P.;Sibley, Christopher R.;Vernia, Santiago
RNA选择性剪接(AS)扩展了真核基因组的调控潜力。调节肝脏特异性AS谱的机制及其对肝功能的贡献还知之甚少。在这里，我们确定了剪接因子RNA结合狐狸蛋白2(RBFOX2)在维持肝脏生脂环境中的胆固醇动态平衡中的关键作用。利用增强的单核苷酸分辨紫外光交联和免疫沉淀，我们确定了RBFOX2在小鼠肝脏中的生理相关靶点，包括清道夫受体B类I(Scar1)。在饮食诱导的肥胖中，RBFox2功能在肝脏中降低，导致Scar1亚型转换和肝细胞脂质平衡的改变。我们的发现表明，特定的AS方案积极维持肝脏生理，并在失调时构成肥胖饮食的脂毒性效应的基础。针对该网络的剪接开关寡核苷酸可减轻肥胖引起的肝脏炎症，并促进血液中抗动脉粥样硬化脂蛋白的表达，突显了异构体特异性RNA疗法用于治疗代谢相关疾病的潜力。Paterson和Yu等人。研究表明，在生脂饮食过程中，肝脏中RNA选择性剪接因子RBFOX2的丢失会通过特定的选择性剪接程序导致肝脏脂质和胆固醇稳态的失调，其中包括高密度脂蛋白受体基因Scar1的剪接开关。
RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases. Paterson and Yu et al. demonstrate that loss of the RNA alternative splicing factor RBFOX2 in the liver during a lipogenic diet leads to dysregulation of liver lipid and cholesterol homeostasis through a specific alternative splicing programme, which includes a splice switch of the high-density lipoprotein receptor gene Scarb1.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
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影响因子：
3.4
作者：
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通讯作者：
Hoopmann, Michael R.
影响因子：
4.5
作者：
Damianov, Andrey;Black, Douglas L.
通讯作者：
Black, Douglas L.
影响因子：
4.8
作者：
Eckhardt, ERM;Cai, L;Van der Westhuyzen, DR
通讯作者：
Van der Westhuyzen, DR
PybedTools：一个灵活的Python库，用于操纵基因组数据集和注释。
DOI：
10.1093/bioinformatics/btr539
发表时间：
2011-12-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Dale RK;Pedersen BS;Quinlan AR
通讯作者：
Quinlan AR