Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites

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 LXRα/β 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.