CMO1 Deficiency Abolishes Vitamin A Production from β-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 β-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 β-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 γ-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. 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 β-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 β-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 γ-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. Dietary lipids are precursors for signaling molecules that control many facets in cell physiology. As the classic example, fat-soluble vitamin A (all-trans-retinol) is essential for processes ranging from development to vision and cell proliferation (1Mark M. Ghyselinck N.B. Chambon P. Annu. Rev. Pharmacol. Toxicol. 2006; 46: 451-480Crossref PubMed Scopus (488) Google Scholar, 2Simoni D. Tolomeo M. Curr. Pharm. Des. 2001; 7: 1823-1837Crossref PubMed Scopus (73) Google Scholar, 3Thompson D.A. Gal A. Prog. Retin. Eye Res. 2003; 22: 683-703Crossref PubMed Scopus (160) Google Scholar). Retinol is the precursor for at least two critical metabolites, 11-cis-retinal, the chromophore of visual G-protein-coupled receptors (4Palczewski K. Annu. Rev. Biochem. 2006; 75: 743-767Crossref PubMed Scopus (555) Google Scholar), and retinoic acid (RA). 5The abbreviations used are: RA, retinoic acid; FFA, serum free fatty acid; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; HPLC, high pressure liquid chromatography; qRT, quantitative real time. 5The abbreviations used are: RA, retinoic acid; FFA, serum free fatty acid; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; HPLC, high pressure liquid chromatography; qRT, quantitative real time. All-trans-RA and 9-cis-RA regulate gene expression via heterodimeric nuclear receptors consisting of an RA receptor and a retinoid X receptor (RXR) (5Petkovich M. Brand N.J. Krust A. Chambon P. Nature. 1987; 330: 444-450Crossref PubMed Scopus (1737) Google Scholar, 6Giguere V. Ong E.S. Segui P. Evans R.M. Nature. 1987; 330: 624-629Crossref PubMed Scopus (1532) Google Scholar). Both are ligand-dependent transcription factors belonging to the superfamily of nuclear hormone receptors (7Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2601) Google Scholar). Additionally, RXRs form heterodimers with other members of the nuclear receptor family (8Shulman A.I. Mangelsdorf D.J. N. Engl. J. Med. 2005; 353: 604-615Crossref PubMed Scopus (331) Google Scholar), including the peroxisome proliferator-activated receptors (PPARs). Because animals, including humans, are unable to synthesize vitamin A de novo, all retinoids (vitamin A and its derivatives) derive from the oxidative cleavage of dietary provitamin A carotenoids, mainly β-carotene (9Olson J.A. Hayaishi O. Proc. Natl. Acad. Sci. U. S. A. 1965; 54: 1364-1370Crossref PubMed Scopus (259) Google Scholar, 10Goodman D.S. Huang H.S. Science. 1965; 149: 879-880Crossref PubMed Scopus (184) Google Scholar, 11Wang X.D. Tang G.W. Fox J.G. Krinsky N.I. Russell R.M. Arch. Biochem. Biophys. 1991; 285: 8-16Crossref PubMed Scopus (211) Google Scholar). How this conversion of β-carotene occurs (centric and/or eccentric cleavage) is still a matter of debate (12Wolf G. Nutr. Rev. 1995; 53: 134-137Crossref PubMed Scopus (34) Google Scholar, 13Wolf G. Nutr. Rev. 2001; 59: 116-118PubMed Google Scholar, 14Krinsky N. Russell R.M. Nutr. Rev. 2001; 59: 309Crossref PubMed Scopus (6) Google Scholar). Recently, two different carotenoid-monooxygenases, CMO1 and CMO2, were molecularly identified in animals, including humans (15von Lintig J. Hessel S. Isken A. Kiefer C. Lampert J.M. Voolstra O. Vogt K. Biochim. Biophys. Acta. 2005; 1740: 122-131Crossref PubMed Scopus (90) Google Scholar). Both belong to a family of structurally related nonheme iron oxygenases, common to all taxa (16Giuliano G. Al-Babili S. von Lintig J. Trends Plant Sci. 2003; 8: 145-149Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 17Moise A.R. von Lintig J. Palczewski K. Trends Plant Sci. 2005; 10: 178-186Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 18Kloer D.P. Ruch S. Al-Babili S. Beyer P. Schulz G.E. Science. 2005; 308: 267-269Crossref PubMed Scopus (220) Google Scholar). Biochemical analyses revealed that CMO1 is a carotenoid-15,15′-oxygenase, which converts β-carotene to retinaldehyde by a centric oxidative cleavage at the C15,C15′ double bond (19von Lintig J. Vogt K. J. Biol. Chem. 2000; 275: 11915-11920Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 20Wyss A. Wirtz G. Woggon W. Brugger R. Wyss M. Friedlein A. Bachmann H. Hunziker W. Biochem. Biophys. Res. Commun. 2000; 271: 334-336Crossref PubMed Scopus (198) Google Scholar, 21Wyss A. Wirtz G.M. Woggon W.D. Brugger R. Wyss M. Friedlein A. Riss G. Bachmann H. Hunziker W. Biochem. J. 2001; 354: 521-529Crossref PubMed Scopus (111) Google Scholar, 22Redmond T.M. Gentleman S. Duncan T. Yu S. Wiggert B. Gantt E. Cunningham Jr., F.X. J. Biol. Chem. 2001; 276: 6560-6565Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 23Blaner W.S. J. Am. Acad. Dermatol. 2001; 45: S129-S135Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 24Lindqvist A. Andersson S. J. Biol. Chem. 2002; 277: 23942-23948Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). From this cleavage product, all biologically active retinoids can be produced by endogenous metabolic pathways, including 11-cis-retinal and RA. The CMO1 gene has been shown to be transcriptionally regulated by the action of PPARs and RXRs in both mice and humans (25Boulanger A. McLemore P. Copeland N.G. Gilbert D.J. Jenkins N.A. Yu S.S. Gentleman S. Redmond T.M. FASEB J. 2003; 17: 1304-1306Crossref PubMed Scopus (87) Google Scholar, 26Gong X. Tsai S.W. Yan B. Rubin L.P. BMC Mol. Biol. 2006; 7: 7Crossref PubMed Scopus (41) Google Scholar). This characteristic indicates a regulatory interlink between carotenoid and fatty acid metabolism at this level. The second carotenoid-metabolizing enzyme, CMO2, catalyzes an eccentric oxidative cleavage of carotenoids, such as β-carotene and lycopene, at the C9′,C10′ double bond (27Kiefer C. Hessel S. Lampert J.M. Vogt K. Lederer M.O. Breithaupt D.E. von Lintig J. J. Biol. Chem. 2001; 276: 14110-14116Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar, 28Hu K.Q. Liu C. Ernst H. Krinsky N.I. Russell R.M. Wang X.D. J. Biol. Chem. 2006; 281: 19327-19338Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). The physiological role of this carotenoid oxygenase is still poorly understood. In most mammals, including humans, dietary provitamin A carotenoids can maintain all vitamin A-dependent physiological functions. But it is still not clear whether dietary vitamin A possess the full biological activity of the provitamin. There is evidence in the literature that carotenoid oxygenases can tissue-specifically impact physiological processes. In Drosophila, mutations in CMO1 are associated with blindness (29von Lintig J. Wyss A. Arch. Biochem. Biophys. 2001; 385: 47-52Crossref PubMed Scopus (87) Google Scholar). In zebrafish, CMO1 is required for RA production in certain developing cells J.M. J. Hessel S. W. Vogt K. von Lintig J. 2003; PubMed Scopus Google Scholar). evidence for that carotenoid produced by eccentric cleavage of such as can gene via PPARs and RXRs O. G. G. E. Tang G. Krinsky N.I. J. Mol. PubMed Scopus Google Scholar). In humans, mutations in carotenoid not been in with physiological to more mammalian carotenoid metabolism and here we and a mouse with a of the CMO1 of and of a CMO1 we used homologous recombination in cells to and of the CMO1 gene by an gene and a were by from a mouse and a of of the CMO1 The were the including of and were from the CMO1 and by an by a between two cells cells from mouse were on in a at and to the of a cell of and were a the of of the the was in a at the cells were The with was were of the were for homologous recombination by two Two that homologous recombination were and and were was to the of the The mice were with to and CMO1-/- mice. of the by and was used to from mouse was both by analysis and by a of different was with the and reverse and reverse of were with was a and was at in and The was with and with at for and all we used mice. the analysis of vitamin A and lipid metabolism β-carotene we used of mice as the analysis of vitamin A and lipid metabolism on the vitamin A-sufficient chow, we used mice as were in with and by the of the were and to and in all the β-carotene of the diet a of vitamin A. In the β-carotene this was with β-carotene The of β-carotene in the was In all other mice were with vitamin A. analysis revealed that this the and The high fat of the with and was from and serum was from the The were to of a was used in a of the we used the in a of of we used an J.M. J. Hessel S. W. Vogt K. von Lintig J. 2003; PubMed Scopus Google Scholar). were and molecules were developed with the of was by the for and and carotenoids were from tissues and tissues were in of and of with a of β-carotene and vitamin A of was to of of was to of carotenoids and retinoids was with The was and the were a of and in of carotenoids and retinoids and of was as (19von Lintig J. Vogt K. J. Biol. Chem. 2000; 275: 11915-11920Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar). for and were in from of and and of the levels of free fatty and in serum and tissues was by the of the of the lipid liver were in lipid was by to the were by of levels were by a to the this of the mice were with a for the of were in and The tissues were on and at were in and in to of were with to the of R. and by to the were in The tissues were in and with a the were with to R. and and N. 1991; for general and Quantitative was from liver and visceral adipose tissues with to the were with the and of the was by of a of was at for was for at and at with reverse The was at for a analysis of the were and and and and and and and As we used and was in a of consisting of and reverse and with an an enzyme for at were for and was In to of we Additionally, a was of genes was to Res. 2001; Scopus Google Scholar, on the of and the of a control and in with a gene are as was used to analyze between the and of were CMO1 and CMO1 gene to be as a in the mouse The mouse CMO1 gene can be at the on the as a at CMO1 is in such as the and A. Wirtz G.M. Woggon W.D. Brugger R. Wyss M. Friedlein A. Riss G. Bachmann H. Hunziker W. Biochem. J. 2001; 354: 521-529Crossref PubMed Scopus (111) Google Scholar, 22Redmond T.M. Gentleman S. Duncan T. Yu S. Wiggert B. Gantt E. Cunningham Jr., F.X. J. Biol. Chem. 2001; 276: 6560-6565Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, A. McLemore P. Copeland N.G. Gilbert D.J. Jenkins N.A. Yu S.S. Gentleman S. Redmond T.M. FASEB J. 2003; 17: 1304-1306Crossref PubMed Scopus (87) Google Scholar). A mouse CMO1 was by of a mouse A was to of and with an and a with and cells cells were for homologous recombination was by analysis The mice were with mice to and CMO1-/- mice. The was identified the and and the gene and The expression of CMO1 was in the liver of CMO1-/- mice as by CMO1-/- mice developed and and were on a mouse chow, a role of CMO1 and β-carotene vitamin A is in CMO1 analyze the of CMO1 deficiency on a diet that provides β-carotene as the major dietary for vitamin we a To endogenous for retinoids in the we control and CMO1-/- to a diet in vitamin A This dietary related to vitamin A deficiency in in control and CMO1-/- were on a diet in vitamin β-carotene the of CMO1 deficiency was CMO1-/- mice not control an orange coloring in visceral adipose A and in adipose and in the and production from β-carotene in we analysis with lipid This analysis β-carotene in CMO1-/- in β-carotene cleavage such as and were and This of β-carotene conversion in CMO1-/- mice was by a of β-carotene levels To the of CMO1 we β-carotene and retinoid and levels in tissues that are to the CMO1 gene In all of levels of β-carotene were as with control vitamin A levels were in CMO1-/- mice as with in the were levels and between CMO1-/- and control Thus, CMO1 deficiency β-carotene metabolism, and the provitamin accumulated in several tissues. as the Dietary for to whether CMO1 deficiency is associated with β-carotene that of CMO1-/- mice a of the lipid of the revealed a control levels analysis of liver of in and and These large for lipids A and analysis revealed that liver vitamin A and was lower as with Instead, β-carotene was in the of CMO1-/- mice This in liver vitamin A was seen by an of the serum and is produced in the liver and in a vitamin A-dependent to vitamin A to tissues N. J. S. W. Palczewski K. W.S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, CMO1-/- mice developed a fatty liver and displayed vitamin A liver β-carotene was as the major dietary for vitamin A. to CMO1 and of the A of the such as RA, can liver fatty acid metabolism (e.g. of RA signaling can liver and A. S. S. T. R. K. T. T. M. S. A. N. H. T. H. G. PubMed Scopus Google Scholar). that CMO1-/- mice developed a fatty liver β-carotene was as the major precursor for vitamin A. we whether this liver can be by mice with vitamin A. To this we and mice on a vitamin A-sufficient of vitamin In a of we for of liver of with different that of lipid were and more in of this analysis revealed that this was not by a characteristic of liver H.S. N. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). a and more we used CMO1-/- mice and and the and dietary CMO1-/- mice elevated levels of lipids as with control Additionally, of CMO1-/- mice more of liver revealed lipid in in CMO1-/- mice not in control not Thus, CMO1-/- mice developed liver on a vitamin A-sufficient To the that CMO1 deficiency with liver vitamin A vitamin A is with the we analysis to retinoid vitamin A and was in the in CMO1-/- and control in both Additionally, levels of in liver were in both and the levels of and β-carotene in the In CMO1-/- we β-carotene serum levels β-carotene was levels in control serum levels were in both and CMO1-/- mice as with in of has been identified as a and gene in mice (25Boulanger A. McLemore P. Copeland N.G. Gilbert D.J. Jenkins N.A. Yu S.S. Gentleman S. Redmond T.M. FASEB J. 2003; 17: 1304-1306Crossref PubMed Scopus (87) Google Scholar). These nuclear receptors an essential role in fatty acid metabolism A. Evans R.M. Mangelsdorf D.J. Science. 2001; PubMed Scopus Google Scholar). retinaldehyde has been shown to diet-induced by activity O. G. M. J. J.A. Tang G. S. G. J. Med. PubMed Scopus Google Scholar). is the precursor for RA and which RA receptors and putative β-carotene cleavage can as as in cell O. G. G. E. Tang G. Krinsky N.I. J. Mol. PubMed Scopus Google Scholar). expression in the liver and visceral adipose of both CMO1-/- and control we whether the expression of genes in fatty acid metabolism is altered in CMO1 To this we analysis for genes of both fatty acid and In the levels of were between acid levels were elevated in CMO1-/- mice. acid and levels were the in the different In levels of were in of CMO1-/- mice. the levels of genes in visceral adipose This analysis revealed that levels of the fatty and the receptor were elevated in CMO1-/- mice. Thus, CMO1-/- mice altered expression of genes in fatty acid metabolism in the liver and levels of genes in visceral adipose tissues. of and to liver as we here in CMO1-/- is related to and/or J. PubMed Scopus Google Scholar). we serum of metabolism. levels were between the with revealed in and levels between and levels of a marker for liver R.M. J. H. J. PubMed Scopus Google Scholar), were in the mutant levels of unesterified serum free fatty were elevated in CMO1-/- mice the of of is and is to its serum A. K. A. Rev. 2002; PubMed Scopus Google Scholar), this characteristic the liver in this mouse CMO1-/- mice in fatty acid metabolism, we whether CMO1-/- mice are more susceptible to diet-induced To this we used CMO1-/- and control mice The of mice was at the of the were with the with fat in the form of a of CMO1-/- mice more as with control of the lipid of that it in both more in CMO1-/- mice As liver revealed that large which were more in and in CMO1-/- as with control of serum lipids revealed that were lower in mice dietary between serum levels were in CMO1-/- mice and with lipid in the the levels of serum were as in CMO1-/- mice with the vitamin A from certain carotenoids with provitamin A the role of vitamin A is in cell physiological is the impact of the provitamin A on processes. Recently, two different carotenoid-cleaving CMO1 and CMO2, been molecularly identified in mammals, including humans T.M. Gentleman S. Duncan T. Yu S. Wiggert B. Gantt E. Cunningham Jr., F.X. J. Biol. Chem. 2001; 276: 6560-6565Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 23Blaner W.S. J. Am. Acad. Dermatol. 2001; 45: S129-S135Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 24Lindqvist A. Andersson S. J. Biol. Chem. 2002; 277: 23942-23948Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, C. Hessel S. Lampert J.M. Vogt K. Lederer M.O. Breithaupt D.E. von Lintig J. J. Biol. Chem. 2001; 276: 14110-14116Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). expression of enzymes in tissues that vitamin A to carotenoids tissue-specifically vitamin A-dependent processes. here a mouse with a of the CMO1 gene to more β-carotene metabolism and functions. On a diet providing β-carotene as major retinoid precursor, mutant mice accumulated the provitamin in large quantities in several tissues by a in vitamin A In such β-carotene vitamin A levels were This between was in β-carotene metabolism. in CMO1-/- mice large of dietary β-carotene in of retinoids were with this of β-carotene conversion to serum levels of the provitamin were in CMO1-/- mice and levels to This indicates that CMO1 in the a major role in the conversion of β-carotene to retinoids in the β-carotene was in control Thus, provitamin A in CMO1-/- mice the that β-carotene tissues can impact physiological processes. In this it is that humans large quantities of β-carotene and can carotenoids in including and of CMO1 was J. Nutr. PubMed Scopus Google Scholar). the that in CMO1 β-carotene in large quantities and retinoid levels that the second carotenoid CMO2, to vitamin A production Besides impairments in β-carotene metabolism, CMO1 deficiency lipid metabolism more In CMO1-/- the liver lipid was and a fatty liver was with large lipid in CMO1 deficiency developed of the vitamin A of the CMO1-/- mice liver liver for vitamin A were β-carotene on a vitamin A-sufficient the dietary the to retinoids was not altered in CMO1-/- liver was with levels of Thus, we evidence that liver is related to CMO1 with this mice with liver vitamin A liver N. J. S. W. Palczewski K. W.S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). On a vitamin A-sufficient chow, liver more with Additionally, we that CMO1-/- mice more a high fat diet was This was associated with a more fatty has been shown to be more susceptible to diet-induced liver mice K. M. E. J.M. 2005; 54: PubMed Scopus Google Scholar). the of CMO1-/- in this mice K. 53: PubMed Scopus Google Scholar). levels were between CMO1-/- and control mice both on the and on the levels in with the serum were in CMO1 deficiency dietary the of of is this liver in CMO1-/- mice. The CMO1 gene has been identified as a and gene (25Boulanger A. McLemore P. Copeland N.G. Gilbert D.J. Jenkins N.A. Yu S.S. Gentleman S. Redmond T.M. FASEB J. 2003; 17: 1304-1306Crossref PubMed Scopus (87) Google Scholar). genes in the of fatty in the liver S.S. T. J. H. Mol. Biol. 1995; PubMed Scopus Google Scholar), and genes in lipid pathways, in Ong E.S. P. A. Evans R.M. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar). CMO1 activity on β-carotene in retinaldehyde This cleavage can be converted to RA. In the RA signaling can fatty acid metabolism as as K. S. J. 2002; PubMed Scopus Google Scholar, N. J.M. K. Nature. 2005; PubMed Scopus Google Scholar, D.J. D.P. S. Mol. 2002; PubMed Scopus Google Scholar). the that liver in CMO1-/- mice is by major impairments in metabolism. CMO1-/- mice in Additionally, levels of essential for fatty acid were and levels were as with deficiency has been shown to diet-induced J.M. M. H. P. J.M. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). Additionally, in the elevated activity a role in the of diet-induced R. A. C. H. S. J. 2006; PubMed Scopus Google Scholar), of CMO1 deficiency on the of metabolism more analysis in that RA signaling a role for In cell an of has been in serum W. PubMed Scopus Google Scholar). the a between and RA signaling is A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. Mol. Biol. 1996; PubMed Google Scholar). not RA which from β-carotene cleavage via has been to In elevated retinaldehyde levels in can diet-induced O. G. M. J. J.A. Tang G. S. G. J. Med. PubMed Scopus Google Scholar). in CMO1 levels of such as and were in visceral adipose tissues. our a in which CMO1 expression in to the production of β-carotene cleavage such as retinaldehyde and/or RA. These β-carotene the between nuclear receptors that regulate fatty acid metabolism by In the second carotenoid cleavage enzyme, CMO2, must be in this This enzyme is in the liver as shown in adipose tissues. catalyzes an eccentric cleavage of carotenoid cleavage can and as as in cell O. G. G. E. Tang G. Krinsky N.I. J. Mol. PubMed Scopus Google Scholar). we evidence that to the conversion of the of β-carotene accumulated in CMO1 that signaling molecules are required in we the that activity on β-carotene the activity of nuclear in our we used of activity on other carotenoids different from β-carotene must be it has been shown that A carotenoids, such as lycopene, can and CMO1 expression in S. Jr., J. Nutr. 2006; PubMed Scopus Google Scholar). In our study identifies CMO1 as the key enzyme for the conversion of β-carotene to vitamin A in In we evidence that carotenoids via lipid metabolism more In the CMO1-/- mice a to the essential in this Carotenoids in are the major for vitamin A in humans, and vitamin A deficiency is still a the for a of carotenoid metabolism and is of for for on the are to for of serum lipid the members of the the for