Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites.

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Huq MD, Tsai NP, Gupta P, Wei LN

Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites.

EMBO J. 2006 Jul 12;25(13):3203-13. Epub 2006 Jun 8.

PubMed ID

16763553 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Vitamin A	Retinal dehydrogenase 1	Protein	Humans	Unknown	Substrate	Details