Coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake.
Coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake.
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DOI：
10.1371/journal.pone.0019420
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Krauss RM
中科院分区：
文献类型：
--
作者：
Medina MW;Gao F;Naidoo D;Rudel LL;Temel RE;McDaniel AL;Marshall SM;Krauss RM
参与胆固醇生物合成和摄取的基因以协调的方式响应细胞甾醇含量进行转录调节。其中许多基因，包括 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 和 LDL 受体 (LDLR)，会发生选择性剪接，导致酶或蛋白质活性降低。在这里，我们证明细胞甾醇消耗会抑制参与维持胆固醇稳态的多个基因的选择性剪接，而甾醇加载会诱导这些基因的选择性剪接，包括 HMGCR 和 LDLR，它们分别是细胞胆固醇生物合成和摄取的关键调节因子。这些变化在 HepG2 人肝癌细胞系的体外研究以及圣基茨黑长尾猴（也称为非洲绿猴）的体内研究中观察到，后者是研究胆固醇代谢的常用灵长类动物模型。这些效应部分是由多聚嘧啶束结合蛋白 1 (PTBP1) 的甾醇调节介导的，因为 PTBP1 的敲除消除了甾醇诱导的其中几个基因的选择性剪接的变化。影响 HMGCR 和 LDLR 选择性剪接（分别为 rs3846662 和 rs688）的单核苷酸多态性 (SNP) 与血浆 LDL 胆固醇水平的变化有关。甾醇诱导的选择性剪接变化在每个 SNP 的次要等位基因携带者中减弱，表明该过程的遗传和非遗传调控之间存在相互作用。我们的结果表明，选择性剪接是一种增强对细胞胆固醇消耗或积累条件的稳健转录反应的新机制。因此，选择性剪接的协调调节可能有助于细胞胆固醇稳态以及血浆低密度脂蛋白水平。
Genes involved in cholesterol biosynthesis and uptake are transcriptionally regulated in response to cellular sterol content in a coordinated manner. A number of these genes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR), undergo alternative splicing, resulting in reductions of enzyme or protein activity. Here we demonstrate that cellular sterol depletion suppresses, and sterol loading induces, alternative splicing of multiple genes involved in the maintenance of cholesterol homeostasis including HMGCR and LDLR, the key regulators of cellular cholesterol biosynthesis and uptake, respectively. These changes were observed in both in vitro studies of the HepG2 human hepatoma derived cell line, as well as in vivo studies of St. Kitts vervets, also known as African green monkeys, a commonly used primate model for investigating cholesterol metabolism. These effects are mediated in part by sterol regulation of polypyrimidine tract binding protein 1 (PTBP1), since knock-down of PTBP1 eliminates sterol induced changes in alternative splicing of several of these genes. Single nucleotide polymorphisms (SNPs) that influence HMGCR and LDLR alternative splicing (rs3846662 and rs688, respectively), have been associated with variation in plasma LDL-cholesterol levels. Sterol-induced changes in alternative splicing are blunted in carriers of the minor alleles for each of these SNPs, indicating an interaction between genetic and non-genetic regulation of this process. Our results implicate alternative splicing as a novel mechanism of enhancing the robust transcriptional response to conditions of cellular cholesterol depletion or accumulation. Thus coordinated regulation of alternative splicing may contribute to cellular cholesterol homeostasis as well as plasma LDL levels.
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与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
14.9
作者：
Brunel, F;Zakin, MM;Buckle, M
通讯作者：
Buckle, M
影响因子：
6.5
作者：
Li, Hai;Chen, Wei;Liu, Jingwen
通讯作者：
Liu, Jingwen
DOI：
10.1073/pnas.1534923100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Horton, JD;Shah, NA;Goldstein, JL
通讯作者：
Goldstein, JL
DOI：
10.1073/pnas.84.7.1863
发表时间：
1987-04-01
影响因子：
11.1
作者：
GIL, G;SMITH, JR;BROWN, MS
通讯作者：
BROWN, MS