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PNAS 108 (11): 4340-4345

Copyright © 2011 by the National Academy of Sciences.


Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses

Daniel C. Berrya,b, Hui Jina, Avijit Majumdara, and Noa Noya,b,1

Departments of aPharmacology and bNutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106

Edited* by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved February 1, 2011 (received for review July 28, 2010)

Abstract: It currently is believed that vitamin A, retinol, functions through active metabolites: the visual chromophore 11-cis-retinal, and retinoic acids, which regulate gene transcription. Retinol circulates in blood bound to retinol-binding protein (RBP) and is transported into cells by a membrane protein termed "stimulated by retinoic acid 6" (STRA6). We show here that STRA6 not only is a vitamin A transporter but also is a cell-surface signaling receptor activated by the RBP–retinol complex. Association of RBP-retinol with STRA6 triggers tyrosine phosphorylation, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. The RBP–retinol/STRA6/JAK2/STAT5 signaling cascade induces the expression of STAT target genes, including suppressor of cytokine signaling 3 (SOCS3), which inhibits insulin signaling, and peroxisome proliferator-activated receptor gamma (PPAR{gamma}), which enhances lipid accumulation. These observations establish that the parental vitamin A molecule is a transcriptional regulator in its own right, reveal that the scope of biological functions of the vitamin is broader than previously suspected, and provide a rationale for understanding how RBP and retinol regulate energy homeostasis and insulin responses.

Key Words: retinoids • adipokine • obesity • insulin-resistance

Author contributions: D.C.B., H.J., and N.N. designed research; D.C.B., H.J., and A.M. performed research; D.C.B., H.J., and N.N. analyzed data; and N.N. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: noa.noy{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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