title: A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption.
abstract: Carotenoids are currently investigated regarding their potential to lower the risk of chronic disease and to combat vitamin A deficiency. Surprisingly, responses to dietary supplementation with these compounds are quite variable between individuals. Genome-wide studies have associated common genetic polymorphisms in the BCO1 gene with this variability. The BCO1 gene encodes an enzyme that is expressed in the intestine and converts provitamin A carotenoids to vitamin A-aldehyde. However, it is not clear how this enzyme can impact the bioavailability and metabolism of other carotenoids such as xanthophyll. We here provide evidence that BCO1 is a key component of a regulatory network that controls the absorption of carotenoids and fat-soluble vitamins. In this process, conversion of β-carotene to vitamin A by BCO1 induces via retinoid signaling the expression of the intestinal homeobox transcription factor ISX. Subsequently, ISX binds to conserved DNA-binding motifs upstream of the BCO1 and SCARB1 genes. SCARB1 encodes a membrane protein that facilitates absorption of fat-soluble vitamins and carotenoids. In keeping with its role as a transcriptional repressor, SCARB1 protein levels are significantly increased in the intestine of ISX-deficient mice. This increase results in augmented absorption and tissue accumulation of xanthophyll carotenoids and tocopherols. Our study shows that fat-soluble vitamin and carotenoid absorption is controlled by a BCO1-dependent negative feedback regulation. Thus, our findings provide a molecular framework for the controversial relationship between genetics and fat-soluble vitamin status in the human population.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: M Airanthi K
authors.initials: MA
authors.lastname: Widjaja-Adhi
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Glenn P
authors.initials: GP
authors.lastname: Lobo
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA johannes.vonlintig@case.edu.
authors.forename: Johannes
authors.initials: J
authors.lastname: Von Lintig
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005123:Eye / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007408:Intestinal Absorption; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051122:Scavenger Receptors, Class B / Q000502:physiology; D012995:Solubility; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D024341:Xanthophylls / Q000378:metabolism*; D065146:Zeaxanthins / Q000378:metabolism*
chemical_list: C527930:Isx protein, mouse; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014157:Transcription Factors; D024341:Xanthophylls; D065146:Zeaxanthins