Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites.
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.
Huq
M D Mostaqul
MD
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, 55455, USA.
Tsai
Nien-Pei
NP
Gupta
Pawan
P
Wei
Li-Na
LN
D000445:Aldehyde Oxidoreductases / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors; D017035:Pravastatin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D050697:Retinal Dehydrogenase / Q000096:biosynthesis / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D014212:Tretinoin / Q000378:metabolism*
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014212:Tretinoin; D002784:Cholesterol; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D050697:Retinal Dehydrogenase; D017035:Pravastatin