title: Vitamin A in regulation of insulin responsiveness: mini review.
abstract: Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.
authors.affiliation: Department of Cellular & Molecular Medicine,Lerner Research Institute,Cleveland Clinic,9500 Euclid Avenue, NC-10,Cleveland,Ohio 44195,USA.
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000818:Animals; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009765:Obesity; D011228:Prealbumin / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014801:Vitamin A / Q000097:blood / Q000502:physiology*
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D011228:Prealbumin; C101326:RBP4 protein, human; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C519685:STRA6 protein, human; C108001:Stra6 protein, mouse; D014801:Vitamin A
keywords: CRBP cellular retinol-binding protein; Cytokine signalling; Insulin response; JAK Janus kinases; Janus kinases/signal transducers and activators of transcription; RBP retinol-binding protein; Retinol binding protein; STAT signal transducers and activators of transcription; STRA6 stimulated by retinoic acid 6; TTR transthyretin; Vitamin A