Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites
Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites
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DOI：
10.1038/sj.emboj.7601181
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发表时间：
2006-07-12
期刊：
影响因子：
11.4
通讯作者：
Wei, Li-Na
中科院分区：
文献类型：
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作者：
Huq, M. D. Mostaqul;Tsai, Nien-Pei;Wei, Li-Na
视黄酸（RA）是维生素A的主要活性成分，是各种生物过程所必需的。组织中的RA水平是通过一系列代谢反应来维持的，其中视黄醇脱氢酶（RALDH）催化从视黄醇生物合成RA的终末反应，这是一个限速步骤。我们发现，膳食中添加胆固醇增加了RALDH 1和2基因的表达和重要器官如脑、肾、肝和心脏中的细胞RA含量。降胆固醇药物普伐他汀钠下调RALDH 1和2基因在几个器官，特别是肝脏和培养的肝细胞中的表达。此外，胆固醇代谢物，主要是氧固醇，肝X受体（LXR）的天然配体，通过上调与这些基因的调控区结合的固醇调控元件结合蛋白-1c（SREBP-1c）诱导这些基因。LXR α/B或SREBP-1c的敲低下调RALDH基因的表达，这可以通过重新表达SREBP-1c来挽救，表明SREBP-1c是这些基因的直接正调控因子。这项研究揭示了胆固醇和RA生物合成之间的新串扰。
Retinoic acid (RA) constitutes the major active ingredient of vitamin A and is required for various biological processes. The tissue RA level is maintained through a cascade of metabolic reactions where retinal dehydrogenases (RALDHs) catalyze the terminal reaction of RA biosynthesis from retinal, a rate-limiting step. We showed that dietary supplement of cholesterol enhanced the expression of RALDH1 and 2 genes and the cellular RA content in vital organs such as brain, kidney, liver and heart. Consistently, the cholesterol-lowering agent (pravastatin sodium) downregulated the expression of RALDH1 and 2 genes in several organs especially the liver and in cultured liver cells. Further, cholesterol metabolites, predominantly the oxysterols, the natural ligands for liver X receptor (LXR), induced these genes via upregulation of sterol regulatory element binding protein-1c (SREBP-1c) that bound to the regulatory regions of these genes. Knockdown of LXRa/b or SREBP-1c downregulated the expression of RALDH genes, which could be rescued by re-expressing SREBP-1c, suggesting SREBP-1c as a direct positive regulator for these genes. This study uncovered a novel crosstalk between cholesterol and RA biosynthesis.