Retinol Binding Protein 4: Role in Diabetes and Cancer
Vitamin A, retinol, circulates in blood associated with retinol-binding protein 4 (RBP4). It was reported that the level of circulating RBP4 is often elevated in obese mice and humans and that, under these circumstances, the protein induces insulin resist
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Retinol Binding Protein 4: Role in Diabetes and Cancer Daniel C. Berry and Noa Noy Abstract Vitamin A, retinol, circulates in blood associated with retinol-binding protein 4 (RBP4). It was reported that the level of circulating RBP4 is often elevated in obese mice and humans and that, under these circumstances, the protein induces insulin resistance. Recent studies showed that, in addition to its function as a transport protein, RBP4 serves as a cytokine which, upon binding to a cognate membrane receptor termed STRA6, activates a signaling cascade mediated by the Janus kinase JAK2 and its associated transcription factors STAT3 and STAT5. In turn, activated STATs induce the expression of target genes, some of which are closely involved in the regulation of insulin responsiveness and cancer cell biology. Taken together, available information suggests that through its unexpected activity as a signaling molecule, RBP4 may be a link through which obesity results in insulin resistance and some cancers. Keywords Vitamin A • Retinol-binding protein • Cytokine • Insulin responses • Cancer • JAK • STAT • Intracellular retinoid-binding proteins
Vitamin A: Absorption and Metabolism Vitamin A, retinol, is an essential lipid-soluble factor, which can be obtained from two major dietary sources: animal fat/fish oil and plant material [1, 2]. Retinyl esters, present in animal fat and fish oil, are hydrolyzed in the intestinal lumen to yield free fatty acid and retinol (Fig. 5.1) which is then subsequently taken up by the enterocytes. Carotenoids, present in plant material, are absorbed intact, and, in the enterocyte and other tissues, they can undergo enzymatic cleavage into two
D.C. Berry, Ph.D. Division of Endocrinology, Department of Internal Medicine, Graff Lab, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA e-mail: [email protected] N. Noy, Ph.D. (*) Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected] © Springer International Publishing Switzerland 2017 O. Reizes, N.A. Berger (eds.), Adipocytokines, Energy Balance, and Cancer, Energy Balance and Cancer 12, DOI 10.1007/978-3-319-41677-9_5
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D.C. Berry and N. Noy O O
R
b-carotene
retinylester
OH
retinol
O
retinal
O OH
retinoic acid
Fig. 5.1 Structures of retinol and its precursors and active metabolites
molecules of retinal which is then converted to retinol (Fig. 5.1). Vitamin A is essential for vision, reproduction, embryonic development, immune function, and tissue homeostasis. In the enterocytes, retinol, obtained from either dietary food source, is esterified with a long chain fatty acid to yield retinyl esters. These are packaged in chylomicrons and secreted into the lymphatic system to be delivered through the circulation to tissues that store or utilize vitamin A. Two types of enzymes catalyze the formation of retinyl esters [3, 4]. One of these is lecithin/retinol acyltransferase (LRAT), an enzyme that synthesizes retinyl esters by
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