CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice.
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.
Hessel
Susanne
S
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
Eichinger
Anne
A
DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
Isken
Andrea
A
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
Amengual
Jaume
J
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
Hunzelmann
Silke
S
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
Hoeller
Ulrich
U
DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
Elste
Volker
V
DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
Hunziker
Willi
W
Frimorfo SA, Chemin du Musée, CH-1700 Fribourg, Switzerland.
Goralczyk
Regina
R
DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland.
Oberhauser
Vitus
V
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany.
von Lintig
Johannes
J
Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany. Electronic address: lintig@biologie.uni-freiburg.de.
Wyss
Adrian
A
DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 3255, CH-4002 Basel, Switzerland. Electronic address: adrian.wyss@dsm.com.
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
D005227:Fatty Acids; D008055:Lipids; D047495:PPAR gamma; D019207:beta Carotene; D014801:Vitamin A; D010105:Oxygenases; C500451:carotenoid oxygenase