title: Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX.
abstract: Low dietary intake of β-carotene is associated with chronic disease and vitamin A deficiency. β-Carotene is converted to vitamin A in the intestine by the enzyme β-carotene-15,15'-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence β-carotene metabolism and vitamin A homeostasis. Here we show that the intestine-specific transcription factor ISX binds to the Bcmo1 promoter. Moreover, upon induction by the β-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental β-carotene. The ISX binding site in the human BCMO1 promoter contains a common single nucleotide polymorphism that is associated with decreased conversion rates and increased fasting blood levels of β-carotene. Thus, our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process.
authors: Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
authors: Glenn P
authors: GP
authors: Lobo
authors: Jaume
authors: J
authors: Amengual
authors: Diane
authors: D
authors: Baus
authors: Ramesh A
authors: RA
authors: Shivdasani
authors: Derek
authors: D
authors: Taylor
authors: Johannes
authors: J
authors: von Lintig
mesh_terms: D000821:Animal Feed; D000818:Animals; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000737:chemistry* / Q000378:metabolism; D019207:beta Carotene / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D018398:Homeodomain Proteins; C579132:Isx protein, human; C527930:Isx protein, mouse; D008055:Lipids; D014157:Transcription Factors; D019207:beta Carotene; D014801:Vitamin A; D014212:Tretinoin; D004247:DNA
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