Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewSignaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis☆
Highlights
► Holo-RBP, which transports vitamin A in blood, is a signaling molecule. ► STRA6 functions both as a vitamin A transporter and as a surface signaling receptor activated by holo-RBP. ► Activation of STRA6 by RBP–ROH triggers a JAK/STAT cascade, thereby inducing gene trascription. ► Some genes induced by RBP–ROH/STRA6/JAK/STAT signaling are involved in regulating insulin responses and lipid metabolism.
Introduction
Vitamin A was recognized as an essential factor in foods about a century ago [1], [2] and a substantial body of knowledge on the mechanisms that regulate its absorption and disposition in the body and on its biological functions has since accumulated [3]. The vitamin plays key roles in embryonic development, vision, immune function, and tissue remodeling and metabolism. It is usually believed that most of these functions are exerted not by the parental vitamin A molecule, retinol, but by active metabolites (Fig. 1). Hence,11-cis-retinal mediates phototransduction and is essential for vision, and all-trans-retinoic acid regulates gene transcription by activating the nuclear receptors retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ) [4], [5], [6], [7]. Other retinoids, most notably 9-cis-retinoic acid, display transcriptional activities. However, while this isomer can efficiently activate the nuclear receptor retinoid X receptor (RXR), it has been difficult to establish whether it is in fact present in tissues that express RXR in vivo, other than the pancreas [8]. It thus remains unclear whether 9-cis-retinoic acid is a physiologically meaningful RXR ligand [9].
Vitamin A is obtained from the diet either from animal sources, where it is present in the form of retinylesters, or from plants that contain carotenoids such as β-carotene (Fig. 1). In intestinal absorptive cells, retinol derived from either source is esterified to long chain fatty acids to form retinyesters. Retinylesters are then packaged in chylomicrons, secreted through the lymphatic system into blood and are taken up by the liver. The liver thus serves as the major storage for vitamin A in the body [10]. The mechanisms by which vitamin A needs are “sensed” by the liver and that trigger the release of retinol from its hepatic storage pool are unknown. However, when such a release is induced, retinol is mobilized from the liver bound to a protein called serum retinol binding protein (RBP). Other tissues, including adipose tissues, kidney, lung, heart, skeletal muscle, spleen, eye, and testis express RBP. However, corresponding to its function in vitamin A storage, the liver is the main site of synthesis and secretion of this protein. In blood, retinol-bound RBP is associated with a 55 KDa homotetrameric protein termed transthyretin (transporter of thyroxin and retinol, TTR), which, in addition to binding RBP, transports thyroxin (T4). The ternary retinol/RBP/TTR complex is the circulating vitamin A source for extrahepatic tissues. Uptake of retinol from blood into target cells is mediated by a protein called stimulated by retinoic acid 6 (STRA6), a cell surface transporter which binds RBP and facilitates the movement of retinol from the serum protein into cells [11], [12]. In target cells, retinol can be stored in the form of retinylesters or it can be converted into the transcriptionally active metabolites retinoic acids. In retinal pigment epithelium in the eye, retinol can also be metabolized to 11-cis-retinal which is transported to photoreceptor cells where it serves to regenerate the visual pigment rhodopsin.
It is well documented that vitamin A is involved in lipid metabolism and insulin responses through its ability to activate the nuclear receptors termed retinoic acid receptors (RAR), and peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Upon their activation, these receptors regulate the expression of proteins that control adipocyte differentiation, lipolysis, energy dissipation, fatty acid oxidation, and glucose transport [13], [14], [15], [16], [17], [18]. Indeed, it has long been thought that the only function of RBP is to allow the hydrophobic vitamin A to circulate in blood, and that retinol participates in regulating energy homeostasis and insulin responsiveness solely through serving as a precursor for retinoic acid. However, more recently, it was reported that expression of RBP in adipose tissue and, correspondingly, serum levels of the protein, are markedly increased in obese mice and humans. It was further demonstrated that elevation in serum RBP levels causes insulin resistance [19]. By linking RBP to impairment of insulin responses in obese animals, these observations raise the intriguing possibility that the protein has biological activities other than to serve as the plasma carrier of vitamin A. In pursuing such a possibility, we discovered that association of retinol-bound RBP with the vitamin A transporter STRA6 triggers a signaling cascade mediated by the Janus kinase JAK2 and its associated transcription factors Signal Transducers and Activators of Transcription (STATs). The observations further revealed that activation of a JAK/STAT cascade by RBP–retinol results in upregulation of expression of STAT target genes including genes that inhibit insulin signaling and that control lipid homeostasis. Here, we review available information on the newly found signaling pathway initiated by retinol-bound RBP (holo-RBP). We summarize the observations that led to the surprising conclusions that the circulating RBP–retinol complex regulates gene transcription by a mechanism that is independent of the function of retinol as a precursor for retinoic acid, and that STRA6 functions as a signaling membrane receptor.
Section snippets
The retinol–RBP–TTR complex
Retinol is secreted from the liver into blood bound to RBP, a member of the lipocalin family which includes small, mostly extracellular, proteins found in vertebrate and invertebrate animals, plants, and bacteria. Lipocalins have diverse functions but, like RBP, many of them serve as transporters for small hydrophobic molecules [20], [21]. These proteins share a very low sequence homology but display a highly conserved overall fold. They are comprised of an eight-stranded antiparallel β-sheet
STRA6
The tight interaction of retinol with RBP allows the poorly-soluble vitamin to circulate in plasma. However, target tissues for vitamin A do not take up the protein and, in order to reach the interior of cells, retinol must dissociate from RBP prior to uptake. It has long been postulated that there exists a receptor for RBP which functions to transport retinol from the protein into cells [33], [34], [35]. The identity of such a receptor has remained elusive until a recent report suggested that
JAK/STAT signaling
In animals, from flies to humans, extracellular polypeptides such as cytokines, hormones, growth factors, and at least one adipokine, leptin, function by binding to cognate transmembrane receptors that, in turn, activate a signaling cascade mediated by the transcription factors termed Signal Transducers and Activators of Transcription (STAT) and their associated tyrosine kinases called Janus kinases (JAK). Activation of JAK/STAT pathways induced by extracellular signaling peptides and their
STRA6 transduces RBP–retinol signaling to trigger a JAK/STAT cascade that regulates insulin responses and lipid homeostasis
Previous studies revealed that, in obese and insulin resistant mice, synthesis of RBP in adipose tissue is enhanced and that the protein is secreted from this tissue into blood resulting in a marked elevation in its serum levels. It was further demonstrated that administration of RBP to lean mice leads to insulin resistance, and that mice lacking RBP are protected from insulin resistance induced by a high fat diet. These observations led to the surprising conclusion that RBP functions as an
Open questions
The identification of the novel signaling cascade mediated by RBP–ROH, STRA6, JAK2, and STAT5 establish that STRA6 is not only a vitamin A transporter but also a surface signaling receptor. An important question that remains open is whether the two functions of the receptor are inter-related. Does signaling by STRA6 modulate STRA6-mediated retinol uptake? Conversely, is the uptake necessary for signaling?
Cytokine receptors often communicate with more than one signaling cascades. While it has
Acknowledgements
We thank Hui Jin for important contributions to this work. Work from the authors' laboratory was supported by NIH grants DK060684 and DK088669 to N.N. D.C.B. was partially supported by NIH grant DK073195T32.
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This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.