CMO1 deficiency abolishes vitamin A production from β-carotene and alters lipid metabolism in mice

被引:201
作者
Hessel, Susanne
Eichinger, Anne
Isken, Andrea
Amengual, Jaume
Hunzelmann, Silke
Hoeller, Ulrich
Elste, Volker
Hunziker, Willi
Goralczyk, Regina
Oberhauser, Vitus
von Lintig, Johannes
Wyss, Adrian
机构
[1] Univ Freiburg, Dept Neurobiol & Anim Physiol, Inst Biol 1, D-79104 Freiburg, Germany
[2] DSM Nutr Prod Ltd, R&D Human Nutr & Hlth, CH-4002 Basel, Switzerland
[3] Chemin Musee, Frimorfo SA, CH-1700 Fribourg, Switzerland
关键词
D O I
10.1074/jbc.M706763200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:33553 / 33561
页数:9
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共 55 条
[1]   Genetic determinants of energy expenditure and insulin resistance in diet-induced obesity in mice [J].
Almind, K ;
Kahn, CR .
DIABETES, 2004, 53 (12) :3274-3285
[2]   PPARγ is required for placental, cardiac, and adipose tissue development [J].
Barak, Y ;
Nelson, MC ;
Ong, ES ;
Jones, YZ ;
Ruiz-Lozano, P ;
Chien, KR ;
Koder, A ;
Evans, RM .
MOLECULAR CELL, 1999, 4 (04) :585-595
[3]   Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome [J].
Biddinger, SB ;
Almind, K ;
Miyazaki, M ;
Kokkotou, E ;
Ntambi, JM ;
Kahn, CR .
DIABETES, 2005, 54 (05) :1314-1323
[4]   Cellular metabolism and actions of 13-cis-retinoic acid [J].
Blaner, WS .
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2001, 45 (05) :S129-S135
[5]   Identification of beta-carotene 15,15′-monooxygenase as a peroxisome proliferator-activated receptor target gene [J].
Boulanger, A ;
McLemore, P ;
Copeland, NG ;
Gilbert, DJ ;
Jenkins, NA ;
Yu, SS ;
Gentleman, S ;
Redmond, TM .
FASEB JOURNAL, 2003, 17 (08) :1304-+
[6]   Molecular mediators of hepatic steatosis and liver injury [J].
Browning, JD ;
Horton, JD .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (02) :147-152
[7]   Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma [J].
Campbell, JS ;
Hughes, SD ;
Gilbertson, DG ;
Palmer, TE ;
Holdren, MS ;
Haran, AC ;
Odell, MM ;
Bauer, RL ;
Ren, HP ;
Haugen, HS ;
Yeh, MM ;
Fausto, N .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (09) :3389-3394
[8]   A decade of molecular biology of retinoic acid receptors [J].
Chambon, P .
FASEB JOURNAL, 1996, 10 (09) :940-954
[9]   PEROXISOME PROLIFERATOR AND RETINOID SIGNALING PATHWAYS COREGULATE PREADIPOCYTE PHENOTYPE AND SURVIVAL [J].
CHAWLA, A ;
LAZAR, MA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (05) :1786-1790
[10]   Nuclear receptors and lipid physiology: Opening the X-files [J].
Chawla, A ;
Repa, JJ ;
Evans, RM ;
Mangelsdorf, DJ .
SCIENCE, 2001, 294 (5548) :1866-1870