Provitamin A metabolism and functions in mammalian biology

American Journal of Clinical Nutrition

Volumn 96, Issue 5, 2012, Pages

  Von Lintig, Johannes ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA CAROTENE; BETA CAROTENE; RETINOID; RETINOL; RETINOL DERIVATIVE; TRACE ELEMENT;

ABSORPTION; BIOLOGY; DEVELOPING COUNTRY; DIET; FEEDBACK SYSTEM; GENE; GENETIC POLYMORPHISM; HEALTH; HOMEOSTASIS; HUMAN; MITOCHONDRION; NEGATIVE FEEDBACK; NONHUMAN; OXIDATIVE STRESS; PUBLIC HEALTH PROBLEM; RETINOL DEFICIENCY; REVIEW; VITAMIN INTAKE; VITAMIN METABOLISM;

ANIMALS; BETA CAROTENE; BETA-CAROTENE 15,15'-MONOOXYGENASE; DIOXYGENASES; GENE EXPRESSION REGULATION; HUMANS; INTESTINAL ABSORPTION; MICE; VITAMIN A; VITAMIN A DEFICIENCY;

EID: 84867812997     PISSN: 00029165     EISSN: 19383207     Source Type: Journal    
DOI: 10.3945/ajcn.112.034629     Document Type: Review

References (104)

1. Demmig-Adams B, Adams WW III. Antioxidants in photosynthesis and human nutrition. Science 2002;298:2149-53.
2. Bernstein PS, Yoshida MD, Katz NB, McClane RW, Gellermann W. Raman detection of macular carotenoid pigments in intact human retina. Invest Ophthalmol Vis Sci 1998;39:2003-11. (Pubitemid 28455069)
3. Barker FM II, Snodderly DM, Johnson EJ, Schalch W, Koepcke W, Gerss J, Neuringer M. Nutritional manipulation of primate retinas, V: effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity to blue-light-induced damage. Invest Ophthalmol Vis Sci 2011;52:3934-42.
4. Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr 2003;23:171-201. (Pubitemid 37059721)
5. Moore T. Vitamin A and carotene: VI. The conversion of carotene to vitamin A in vivo. Biochem J 1930;24:692.
6. D'Ambrosio DN, Clugston RD, Blaner WS, Vitamin A. Metabolism. An Update. 2011;3:63-103.
7. Wald G. Molecular basis of visual excitation. Science 1968;162:230-9.
8. Palczewski K. G protein-coupled receptor rhodopsin. Annu Rev Biochem 2006;75:743-67. (Pubitemid 44118051)
9. von Lintig J, Kiser PD, Golczak M, Palczewski K. The biochemical and structural basis for trans-to-cis isomerization of retinoids in the chemistry of vision. Trends Biochem Sci 2010;35:400-10.
10. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996;10:940-54. (Pubitemid 26285969)
11. Palczewski K. Retinoids for treatment of retinal diseases. Trends Pharmacol Sci 2010;31:284-95.
12. Blaner WS. STRA6, a cell-surface receptor for retinol-binding protein: the plot thickens. Cell Metab 2007;5:164-6.
13. Mark M, Ghyselinck NB, Chambon P. Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 2006;46:451-80. (Pubitemid 43271197)
14. Ziouzenkova O, Plutzky J. Retinoid metabolism and nuclear receptor responses: new insights into coordinated regulation of the PPAR-RXR complex. FEBS Lett 2008;582:32-8. (Pubitemid 50019948)
15. Agace WW. T-cell recruitment to the intestinal mucosa. Trends Immunol 2008;29:514-22.
16. Underwood BA. Vitamin A deficiency disorders: international efforts to control a preventable "pox". J Nutr 2004;134:231S-6S. (Pubitemid 38063105)
17. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54. (Pubitemid 34251675)
18. Christian P, West KP Jr, Khatry SK, Katz J, LeClerq SC, Kimbrough-Pradhan E, Dali SM, Shrestha SR. Vitamin A or beta-carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women. J Nutr 2000;130:2675-82.
19. Ye X, Al-Babili S, Kloti A, Zhang J, Lucca P, Beyer P, Potrykus I. Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science 2000;287:303-5. (Pubitemid 30046756)
20. Diretto G, Al-Babili S, Tavazza R, Papacchioli V, Beyer P, Giuliano G. Metabolic engineering of potato carotenoid content through tuber-specific overexpression of a bacterial mini-pathway. PLoS ONE 2007;2:e350.
21. Naqvi S, Zhu C, Farre G, Ramessar K, Bassie L, Breitenbach J, Perez Conesa D, Ros G, Sandmann G, Capell T, et al. Transgenic multivitamin corn through biofortification of endosperm with three vitamins representing three distinct metabolic pathways. Proc Natl Acad Sci USA 2009;106:7762-7.
22. Krinsky NI, Johnson EJ. Carotenoid actions and their relation to health and disease. Mol Aspects Med 2005;26:459-516. (Pubitemid 41741836)
23. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145-9. (Pubitemid 26137972)
24. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35.
25. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5. (Pubitemid 26137973)
26. Stephenson RS, O'Tousa J, Scavarda NJ, Randall LL, Pak WL. Drosophila mutants with reduced rhodopsin content. Symp Soc Exp Biol 1983;36:477-501.
27. Wang T, Montell C. Phototransduction and retinal degeneration in Drosophila. Pflugers Arch 2007;454:821-47. (Pubitemid 46976604)
28. Kiefer C, Sumser E, Wernet MF, Von Lintig J. A class B scavenger receptor mediates the cellular uptake of carotenoids in Drosophila. Proc Natl Acad Sci USA 2002;99:10581-6.
29. Wang T, Jiao Y, Montell C. Dissection of the pathway required for generation of vitamin A and for Drosophila phototransduction. J Cell Biol 2007;177:305-16. (Pubitemid 46658641)
30. Voolstra O, Kiefer C, Hoehne M, Welsch R, Vogt K, von Lintig J. The Drosophila class B scavenger receptor NinaD-I is a cell surface receptor mediating carotenoid transport for visual chromophore synthesis. Biochemistry 2006;45:13429-37. (Pubitemid 44748489)
31. von Lintig J, Dreher A, Kiefer C, Wernet MF, Vogt K. Analysis of the blind Drosophila mutant NinaB identifies the gene encoding the key enzyme for vitamin A formation in vivo. Proc Natl Acad Sci USA 2001;98:1130-5. (Pubitemid 32121198)
32. von Lintig J, Vogt K. Filling the gap in vitamin A research: molecular identification of an enzyme cleaving beta-carotene to retinal. J Biol Chem 2000;275:11915-20. (Pubitemid 30237761)
33. Oberhauser V, Voolstra O, Bangert A, von Lintig J, Vogt K. NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide. Proc Natl Acad Sci USA 2008;105:19000-5.
34. Voolstra O, Oberhauser V, Sumser E, Meyer NE, Maguire ME, Huber A, von Lintig J. NinaB is essential for Drosophila vision but induces retinal degeneration in opsin-deficient photoreceptors. J Biol Chem 2010;285:2130-9.
35. Wang X, Wang T, Jiao Y, von Lintig J, Montell C. Requirement for an enzymatic visual cycle in Drosophila. Curr Biol 2010;20:93-102.
36. van Bennekum A, Werder M, Thuahnai ST, Han CH, Duong P, Williams DL, Wettstein P, Schulthess G, Phillips MC, Hauser H. Class B scavenger receptor-mediated intestinal absorption of dietary beta-carotene and cholesterol. Biochemistry 2005;44:4517-25. (Pubitemid 40403994)
37. During A, Harrison EH. Mechanisms of provitamin A (carotenoid) and vitamin A (retinol) transport into and out of intestinal Caco-2 cells. J Lipid Res 2007;48:2283-94. (Pubitemid 47529570)
38. Reboul E, Klein A, Bietrix F, Gleize B, Malezet-Desmoulins C, Schneider M, Margotat A, Lagrost L, Collet X, Borel P. Scavenger receptor class B type I (SR-BI) is involved in vitamin E transport across the enterocyte. J Biol Chem 2006;281:4739-45. (Pubitemid 43847734)
39. Hauser H, Dyer JH, Nandy A, Vega MA, Werder M, Bieliauskaite E, Weber FE, Compassi S, Gemperli A, Boffelli D, et al. Identification of a receptor mediating absorption of dietary cholesterol in the intestine. Biochemistry 1998;37:17843-50. (Pubitemid 29023939)
40. During A, Hussain MM, Morel DW, Harrison EH. Carotenoid uptake and secretion by CaCo-2 cells: beta-carotene isomer selectivity and carotenoid interactions. J Lipid Res 2002;43:1086-95. (Pubitemid 34760880)
41. Moussa M, Gouranton E, Gleize B, Yazidi CE, Niot I, Besnard P, Borel P, Landrier JF. CD36 is involved in lycopene and lutein uptake by adipocytes and adipose tissue cultures. Mol Nutr Food Res 2011;55(4):578-84.
42. Redmond TM, Gentleman S, Duncan T, Yu S, Wiggert B, Gantt E, Cunningham FX Jr. Identification, expression, and substrate specificity of a mammalian beta-carotene 15,15′-dioxygenase. J Biol Chem 2001;276:6560-5.
43. Paik J, During A, Harrison EH, Mendelsohn CL, Lai K, Blaner WS. Expression and characterization of a murine enzyme able to cleave beta-carotene: the formation of retinoids. J Biol Chem 2001;276:32160-8.
44. Wyss A, Wirtz G, Woggon W, Brugger R, Wyss M, Friedlein A, Bachmann H, Hunziker W. Cloning and expression of beta,betacarotene 15,15′- dioxygenase. Biochem Biophys Res Commun 2000;271:334-6.
45. Lindqvist A, Andersson S. Biochemical properties of purified recombinant human beta-carotene 15,15′-monooxygenase. J Biol Chem 2002;277:23942-8. (Pubitemid 34952239)
46. Hessel S, Eichinger A, Isken A, Amengual J, Hunzelmann S, Hoeller U, Elste V, Hunziker W, Goralczyk R, Oberhauser V, et al. CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem 2007;282:33553-61. (Pubitemid 350159522)
47. Lindqvist A, Sharvill J, Sharvill DE, Andersson S. Loss-of-function mutation in carotenoid 15,15′-monooxygenase identified in a patient with hypercarotenemia and hypovitaminosis A. J Nutr 2007;137:2346-50. (Pubitemid 350058699)
48. Leung WC, Hessel S, Meplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G. Two common single nucleotide polymorphisms in the gene encoding β-carotene 15,15'-monoxygenase alter β-carotene metabolism in female volunteers. FASEB J 2009;23:1041-53.
49. Ferrucci L, Perry JR, Matteini A, Perola M, Tanaka T, Silander K, Rice N, Melzer D, Murray A, Cluett C, et al. Common variation in the beta-carotene 15,15′-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study. Am J Hum Genet 2009;84:123-33.
50. Hamel CP, Tsilou E, Pfeffer BA, Hooks JJ, Detrick B, Redmond TM. Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. J Biol Chem 1993;268:15751-7. (Pubitemid 23222076)
51. Mata NL, Moghrabi WN, Lee JS, Bui TV, Radu RA, Horwitz J, Travis GH. Rpe65 is a retinyl ester binding protein that presents insoluble substrate to the isomerase in retinal pigment epithelial cells. J Biol Chem 2004;279:635-43. (Pubitemid 38044868)
52. Xue L, Gollapalli DR, Maiti P, Jahng WJ, Rando RR. A palmitoylation switch mechanism in the regulation of the visual cycle. Cell 2004;117:761-71. (Pubitemid 38748892)
53. Jin M, Li S, Moghrabi WN, Sun H, Travis GH. Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 2005;122:449-59. (Pubitemid 41127145)
54. Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci USA 2005;102:12413-8. (Pubitemid 41266373)
55. Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA 2005;102:13658-63. (Pubitemid 41420904)
56. Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, et al. Mutations in RPE65 cause Leber's congenital amaurosis. Nat Genet 1997;17:139-41.
57. Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 1998;20:344-51. (Pubitemid 28541631)
58. Samardzija M, von Lintig J, Tanimoto N, Oberhauser V, Thiersch M, Reme CE, Seeliger M, Grimm C, Wenzel A. R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal. Hum Mol Genet 2008;17:281-92.
59. Woodruff ML, Wang Z, Chung HY, Redmond TM, Fain GL, Lem J. Spontaneous activity of opsin apoprotein is a cause of Leber congenital amaurosis. Nat Genet 2003;35:158-64. (Pubitemid 37187634)
60. Samardzija M, Tanimoto N, Kostic C, Beck S, Oberhauser V, Joly S, Thiersch M, Fahl E, Arsenijevic Y, von Lintig J, et al. In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death. Hum Mol Genet 2009;18:1266-75.
61. Kiefer C, Hessel S, Lampert JM, Vogt K, Lederer MO, Breithaupt DE, von Lintig J. Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A. J Biol Chem 2001;276:14110-6.
62. Hu KQ, Liu C, Ernst H, Krinsky NI, Russell RM, Wang XD. The biochemical characterization of ferret carotene-9′,10′-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem 2006;281:19327-38. (Pubitemid 44035438)
63. Mein JR, Dolnikowski GG, Ernst H, Russell RM, Wang XD. Enzymatic formation of apo-carotenoids from the xanthophyll carotenoids lutein, zeaxanthin and beta-cryptoxanthin by ferret carotene-9′,10′- monooxygenase. Arch Biochem Biophys 2011;506:109-21.
64. Amengual J, Lobo GP, Golczak M, Li HN, Klimova T, Hoppel CL, Wyss A, Palczewski K, von Lintig J. A mitochondrial enzyme degrades carotenoids and protects against oxidative stress. FASEB J 2011;25:948-59.
65. Tian R, Pitchford WS, Morris CA, Cullen NG, Bottema CD. Genetic variation in the beta, beta-carotene-9′,10′-dioxygenase gene and association with fat colour in bovine adipose tissue and milk. Anim Genet 2010;41:253-9.
66. Berry SD, Davis SR, Beattie EM, Thomas NL, Burrett AK, Ward HE, Stanfield AM, Biswas M, Ankersmit-Udy AE, Oxley PE, et al. Mutation in bovine beta-carotene oxygenase 2 affects milk color. Genetics 2009;182:923-6.
67. Våge DI, Boman IA. A nonsense mutation in the beta-carotene oxygenase 2 (BCO2) gene is tightly associated with accumulation of carotenoids in adipose tissue in sheep (Ovis aries). BMC Genet 2010;11:10.
68. Eriksson J, Larson G, Gunnarsson U, Bed'hom B, Tixier-Boichard M, Stromstedt L, Wright D, Jungerius A, Vereijken A, Randi E, et al. Identification of the yellow skin gene reveals a hybrid origin of the domestic chicken. PLoS Genet 2008;4:e1000010.
69. Ford NA, Clinton SK, von Lintig J, Wyss A, Erdman JW Jr. Loss of carotene-9',10'-monooxygenase expression increases serum and tissue lycopene concentrations in lycopene-fed mice. J Nutr 2010;140:2134-8.
70. von Lintig J, Hessel S, Isken A, Kiefer C, Lampert JM, Voolstra O, Vogt K. Towards a better understanding of carotenoid metabolism in animals. Biochim Biophys Acta 2005;1740:122-31.
71. Paik J, Vogel S, Quadro L, Piantedosi R, Gottesman M, Lai K, Hamberger L, Vieira Mde M, Blaner WS. Vitamin A: overlapping delivery pathways to tissues from the circulation. J Nutr 2004;134:276S-80S. (Pubitemid 38057462)
72. van Bennekum AM, Kako Y,Weinstock PH, Harrison EH, Deckelbaum RJ, Goldberg IJ, Blaner WS. Lipoprotein lipase expression level influences tissue clearance of chylomicron retinyl ester. J Lipid Res 1999;40:565-74. (Pubitemid 29116160)
73. Goodman DW, Huang HS, Shiratori T. Tissue distribution and metabolism of newly absorbed vitamin A in the rat. J Lipid Res 1965;6:390-6.
74. Packer L. Carotenoids and retinoids: molecular aspects and health issues. Champaign, IL: AOCS Press, 2005.
75. Soprano DR, Blaner WS. Plasma retinol binding orotein. In: Sporn MB, Roberts AB, Goodman DS, eds. The retinoids: biology, chemistry, and medicine. 2nd ed. New York, NY: Raven Press, 1994.
76. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P,Wiita P, Bok D, Sun H. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin a. Science 2007;315:820-5.
77. Isken A, Golczak M, Oberhauser V, Hunzelmann S, Driever W, Imanishi Y, Palczewski K, von Lintig J. RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew- Wood syndrome. Cell Metab 2008;7:258-68. (Pubitemid 351285530)
78. Bouillet P, Sapin V, Chazaud C, Messaddeq N, Decimo D, Dolle P, Chambon P. Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein. Mech Dev 1997;63:173-86. (Pubitemid 27272702)
79. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002;23:201-29. (Pubitemid 34299024)
80. Seino Y, Miki T, Kiyonari H, Abe T, Fujimoto W, Kimura K, Takeuchi A, Takahashi Y, Oiso Y, Iwanaga T, et al. Isx participates in the maintenance of vitamin A metabolism by regulation of beta-carotene 15,15′-monooxygenase (Bcmo1) expression. J Biol Chem 2008;283:4905-11.
81. Lobo GP, Hessel S, Eichinger A, Noy N, Moise AR, Wyss A, Palczewski K, von Lintig J. ISX is a retinoic acid-sensitive gate-keeper that controls intestinal beta,beta-carotene absorption and vitamin A production. FASEB J 2010;24:1656-66.
82. Castenmiller JJ, West CE. Bioavailability and bioconversion of carotenoids. Annu Rev Nutr 1998;18:19-38. (Pubitemid 28366859)
83. Johnson EJ, Russell RM. Distribution of orally administered betacarotene among lipoproteins in healthy men. Am J Clin Nutr 1992;56:128-35.
84. Yan W, Jang GF, Haeseleer F, Esumi N, Chang J, Kerrigan M, Campochiaro M, Campochiaro P, Palczewski K, Zack DJ. Cloning and characterization of a human beta,beta-carotene-15,15′-dioxygenase that is highly expressed in the retinal pigment epithelium. Genomics 2001;72:193-202. (Pubitemid 32242959)
85. Lindqvist A, He YG, Andersson S. Cell type-specific expression of beta-carotene 9′,10′-monooxygenase in human tissues. J Histochem Cytochem 2005;53:1403-12. (Pubitemid 41513072)
86. Chichili GR, Nohr D, Schaffer M, von Lintig J, Biesalski HK. beta- Carotene conversion into vitamin A in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2005;46:3562-9. (Pubitemid 44264657)
87. Kim YK, Wassef L, Chung S, Jiang H, Wyss A, Blaner WS, Quadro L: β-Carotene and its cleavage enzyme β-carotene-15,15′-oxygenase (CMOI) affect retinoid metabolism in developing tissues. FASEB J 2011;25(5):1641-52.
88. Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, Freeman S, Cosma MP, Colantuoni V, Gottesman ME. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 1999;18:4633-44. (Pubitemid 29415518)
89. Lampert JM, Holzschuh J, Hessel S, Driever W, Vogt K, Von Lintig J. Provitamin A conversion to retinal via the beta,beta-carotene-15,15'- oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis. Development 2003;130:2173-86. (Pubitemid 36656713)
90. Boulanger A, McLemore P, Copeland NG, Gilbert DJ, Jenkins NA, Yu SS, Gentleman S, Redmond TM. Identification of beta-carotene 15,15′- monooxygenase as a peroxisome proliferator-activated receptor target gene. FASEB J 2003;17:1304-6.
91. Amengual J, Gouranton E, van Helden YG, Hessel S, Ribot J, Kramer E, Kiec-Wilk B, Razny U, Lietz G, Wyss A, et al. Beta-carotene reduces body adiposity of mice via BCMO1. PLoS ONE 2011;6:e20644.
92. Lobo GP, Amengual J, Li HN, Golczak M, Bonet ML, Palczewski K, von Lintig J. β,β-Carotene decreases peroxisome proliferator receptor γ activity and reduces lipid storage capacity of adipocytes in a β,βcarotene oxygenase 1-dependent manner. J Biol Chem 2010;285:27891-9.
93. Schwarz EJ, Reginato MJ, Shao D, Krakow SL, Lazar MA. Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription. Mol Cell Biol 1997;17:1552-61. (Pubitemid 27097385)
94. Puigserver P, Vazquez F, Bonet ML, Pico C, Palou A. In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid. Biochem J 1996;317:827-33. (Pubitemid 26308257)
95. Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol 2009;29:3286-96.
96. O'Byrne SM, Wongsiriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, Palczewski K, Blaner WS. Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). J Biol Chem 2005;280:35647-57. (Pubitemid 41532758)
97. Amengual J, Lobo GP, Golczak M, Li HN, Klimova T, Hoppel CL, Wyss A, Palczewski K, von Lintig J: A mitochondrial enzyme degrades carotenoids and protects against oxidative stress. FASEB J.
98. Yonekura L, Kobayashi M, Terasaki M, Nagao A. Keto-carotenoids are the major metabolites of dietary lutein and fucoxanthin in mouse tissues. J Nutr 2010;140:1824-31.
99. He M, Cornelis MC, Kraft P, van Dam RM, Sun Q, Laurie CC, Mirel DB, Chasman DI, Ridker PM, Hunter DJ, et al. Genome-wide association study identifies variants at the IL18-BCO2 locus associated with interleukin-18 levels. Arterioscler Thromb Vasc Biol 2010;30:885-90.
100. Wang SS, Schadt EE, Wang H, Wang X, Ingram-Drake L, Shi W, Drake TA, Lusis AJ. Identification of pathways for atherosclerosis in mice: integration of quantitative trait locus analysis and global gene expression data. Circ Res 2007;101:e11-30. (Pubitemid 47344081)
101. Paolini M, Antelli A, Pozzetti L, Spetlova D, Perocco P, Valgimigli L, Pedulli GF, Cantelli-Forti G. Induction of cytochrome P450 enzymes and over-generation of oxygen radicals in beta-carotene supplemented rats. Carcinogenesis 2001;22:1483-95. (Pubitemid 32898706)
102. Liu C, Wang XD, Bronson RT, Smith DE, Krinsky NI, Russell RM. Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. Carcinogenesis 2000;21:2245-53. (Pubitemid 32049231)
103. Gallicchio L, Boyd K, Matanoski G, Tao XG, Chen L, Lam TK, Shiels M, Hammond E, Robinson KA, Caulfield LE, et al. Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin Nutr 2008;88:372-83.
104. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842-57. (Pubitemid 46333949)