Huq M D Mostaqul, Tsai Nien-Pei, Gupta Pawan, Wei Li-Na
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, 55455, USA.
EMBO J. 2006 Jul 12;25(13):3203-13. doi: 10.1038/sj.emboj.7601181. Epub 2006 Jun 8.
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 LXRalpha/beta 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.
视黄酸（RA）是维生素A的主要活性成分，参与多种生物学过程。组织中的RA水平通过一系列代谢反应维持，其中视网膜脱氢酶（RALDHs）催化从视黄醛合成RA的末端反应，这是一个限速步骤。我们发现，膳食补充胆固醇可增强RALDH1和2基因的表达以及脑、肾、肝和心脏等重要器官中的细胞RA含量。同样，降胆固醇药物（普伐他汀钠）可下调多个器官尤其是肝脏以及培养的肝细胞中RALDH1和2基因的表达。此外，胆固醇代谢产物，主要是氧甾醇，作为肝脏X受体（LXR）的天然配体，通过上调与这些基因调控区域结合的固醇调节元件结合蛋白-1c（SREBP-1c）来诱导这些基因。敲低LXRα/β或SREBP-1c可下调RALDH基因的表达，重新表达SREBP-1c可使其恢复，这表明SREBP-1c是这些基因的直接正向调节因子。本研究揭示了胆固醇与RA生物合成之间的一种新的相互作用。
