-Apo-10-carotenoids Modulate Placental Microsomal Triglyceride Transfer Protein Expression and Function to Optimize Transport of Intact -Carotene to the Embryo * Received for publication, May 14, 2016, and in revised form, July 5, 2016 Published, JBC Papers in Press, July 8, 2016, DOI 10.1074/jbc.M116.738336 Brianna K. Costabile ‡ , Youn-Kyung Kim ‡ , Jahangir Iqbal § , Michael V. Zuccaro ‡ , Lesley Wassef ‡ , Sureshbabu Narayanasamy ¶ , Robert W. Curley, Jr. ¶ , Earl H. Harrison  , M. Mahmood Hussain §1 , and Loredana Quadro ‡2 From the ‡ Department of Food Science and Rutgers Center for Lipid Research and New Jersey Institute for Food Nutrition and Health, Rutgers University, New Brunswick, New Jersey 08901, § Departments of Cell Biology and Pediatrics, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York 11203, and ¶ College of Pharmacy and  Department of Human Nutrition, The Ohio State University, Columbus, Ohio 43210 -Carotene is an important source of vitamin A for the mam- malian embryo, which depends on its adequate supply to achieve proper organogenesis. In mammalian tissues, -carotene 15,15-oxygenase (BCO1) converts -carotene to retinalde- hyde, which is then oxidized to retinoic acid, the biologically active form of vitamin A that acts as a transcription factor ligand to regulate gene expression. -Carotene can also be cleaved by -carotene 9,10-oxygenase (BCO2) to form -apo-10-carote- nal, a precursor of retinoic acid and a transcriptional regulator per se. The mammalian embryo obtains -carotene from the maternal circulation. However, the molecular mechanisms that enable its transfer across the maternal-fetal barrier are not understood. Given that -carotene is transported in the adult bloodstream by lipoproteins and that the placenta acquires, assembles, and secretes lipoproteins, we hypothesized that the aforementioned process requires placental lipoprotein biosyn- thesis. Here we show that -carotene availability regulates tran- scription and activity of placental microsomal triglyceride transfer protein as well as expression of placental apolipopro- tein B, two key players in lipoprotein biosynthesis. We also show that -apo-10-carotenal mediates the transcriptional regulation of microsomal triglyceride transfer protein via hepatic nuclear factor 4 and chicken ovalbumin upstream pro- moter transcription factor I/II. Our data provide the first in vivo evidence of the transcriptional regulatory activity of -apocaro- tenoids and identify microsomal triglyceride transfer protein and its transcription factors as the targets of their action. This study demonstrates that -carotene induces a feed-forward mechanism in the placenta to enhance the assimilation of -car- otene for proper embryogenesis. The importance of vitamin A as a critical modulator of mam- malian embryonic development has been known for decades (1). This essential nutrient exerts its function mainly through its active form, retinoic acid. Retinoic acid binds to retinoic acid receptors and retinoid X receptors (RXRs) 3 and regulates, in a spatial and temporal manner, the transcription of numerous genes vital to development (2– 6). The mammalian embryo obtains retinoids (vitamin A and its derivatives) and provitamin A carotenoids from the maternal bloodstream. Among dietary carotenoids, -carotene (BC) is the main source of vitamin A for the majority of the world population (7). Intact BC from the maternal circulation crosses the placenta and reaches the developing embryo where the cytoplasmic -carotene 15,15'-oxygenase (BCO1) cleaves BC symmetrically to yield retinaldehyde, which in turn is oxidized to retinoic acid (8, 9). Asymmetric cleavage of BC by -carotene 9',10'-oxygenase (BCO2) also occurs, generating -ionone and -apo-10'-carotenal (apo10AL) (9). The latter, as well as other -apocarotenoids of various chain lengths generated from oxi- dative breakdown of BC in food and animal tissues (10), can be converted into one molecule of retinaldehyde by BCO1 (9, 11). However, BCO2 does not contribute significantly to the gener- ation of retinoids from BC at least in adult tissues (9). Instead, BCO2, which has a broader substrate specificity than BCO1 (7), seems to prevent toxic accumulation of carotenoids, including BC, in mitochondria where the asymmetric cleavage enzyme is localized (8, 12). Interestingly, -apocarotenoids have also been recently found to function as transcriptional regulators, specif- ically as nuclear receptor antagonists, exerting anti-retinoic acid activities (13–17). * This work was supported in part by National Institutes of Health Grants R01HD057493, R01HD057493-02S1, R01HD057493-05S1, and R01HD833331 (to L. Q.); R01HL95924 and R01DK81879 (to M. M. H.); and R01HL049879 (to E. H. H. and R. W. C.) and by Veterans Affairs Merit Award BX001728 (to M. M. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon- sibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 1 To whom correspondence may be addressed. Tel.: 718-270-4790; E-mail: mahmood.hussain@downstate.edu. 2 To whom correspondence may be addressed. Tel.: 848-932-5491; E-mail: quadro@aesop.rutgers.edu. 3 The abbreviations used are: RXR, retinoid X receptor; apoB, apolipoprotein B; apo10AL, -apo-10'-carotenal; apo10OL, -apo-10'-carotenol; BC, -carotene; BCO1, -carotene 15,15'-oxygenase; BCO2, -carotene 9',10'- oxygenase; COUP-TFI/II, chicken ovalbumin upstream promoter transcrip- tion factor I/II; Cyp26A1, cytochrome p450 family 26 subfamily A polypep- tide 1; DR-1, direct repeat 1; Fox, forkhead box protein; Lrh-1, liver receptor homolog 1; MTP, microsomal triglyceride transfer protein (Mttp, MTP gene); NCOR1, nuclear receptor co-repressor 1; PPAR, peroxisome prolif- erator-activated receptor; Pgc1/, peroxisome proliferator-activated receptor  coactivator 1/; qPCR, quantitative real time PCR; Shp, small heterodimer partner; SREBP, sterol regulatory element-binding protein; HNF, hepatic nuclear factor; dpc, day(s) postcoitum; RARE, retinoic acid- responsive element. crossmark THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 291, NO. 35, pp. 18525–18535, August 26, 2016 © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. 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