title: CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice.
abstract: Carotenoids are currently investigated regarding their potential to lower the risk of chronic disease and to combat vitamin A deficiency in humans. These plant-derived compounds must be cleaved and metabolically converted by intrinsic carotenoid oxygenases to support the panoply of vitamin A-dependent physiological processes. Two different carotenoid-cleaving enzymes were identified in mammals, the classical carotenoid-15,15'-oxygenase (CMO1) and a putative carotenoid-9',10'-oxygenase (CMO2). To analyze the role of CMO1 in mammalian physiology, here we disrupted the corresponding gene by targeted homologous recombination in mice. On a diet providing beta-carotene as major vitamin A precursor, vitamin A levels fell dramatically in several tissues examined. Instead, this mouse mutant accumulated the provitamin in large quantities (e.g. as seen by an orange coloring of adipose tissues). Besides impairments in beta-carotene metabolism, CMO1 deficiency more generally interfered with lipid homeostasis. Even on a vitamin A-sufficient chow, CMO1(-/-) mice developed a fatty liver and displayed altered serum lipid levels with elevated serum unesterified fatty acids. Additionally, this mouse mutant was more susceptible to high fat diet-induced impairments in fatty acid metabolism. Quantitative reverse transcription-PCR analysis revealed that the expression of peroxisome proliferator-activated receptor gamma-regulated marker genes related to adipogenesis was elevated in visceral adipose tissues. Thus, our study identifies CMO1 as the key enzyme for vitamin A production and provides evidence for a role of carotenoids as more general regulators of lipid metabolism.
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hessel
authors.affiliation: DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Eichinger
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Isken
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
authors.forename: Jaume
authors.initials: J
authors.lastname: Amengual
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Hunzelmann
authors.affiliation: DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hoeller
authors.affiliation: DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Elste
authors.affiliation: Frimorfo SA, Chemin du Musée, CH-1700 Fribourg, Switzerland.
authors.forename: Willi
authors.initials: W
authors.lastname: Hunziker
authors.affiliation: DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Goralczyk
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
authors.forename: Vitus
authors.initials: V
authors.lastname: Oberhauser
authors.affiliation: Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany. Electronic address: lintig@biologie.uni-freiburg.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.affiliation: DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland. Electronic address: adrian.wyss@dsm.com.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wyss
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D010105:Oxygenases / Q000737:chemistry* / Q000172:deficiency / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism; D011995:Recombination, Genetic; D014801:Vitamin A / Q000378:metabolism*; D019207:beta Carotene / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D008055:Lipids; D047495:PPAR gamma; D019207:beta Carotene; D014801:Vitamin A; D010105:Oxygenases; C500451:carotenoid oxygenase