Journal Article

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

Berry, Daniel C, Noy, Noa, Majumdar, Avijit, Jin, Hui

2011

Overview

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 (PPARγ), 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adipocytes / Animals / Binding sites / Biological Sciences / Blood / Cells / Chromophores / Cytokines / energy / Energy balance / Enzyme Activation - drug effects / Gene expression / Gene Expression Regulation - drug effects / Genes / Hep G2 Cells / Homeostasis / Humans / Insulin / Insulin - metabolism / Janus kinase 2 / Janus Kinase 2 - metabolism / Lipids / Membrane proteins / Membrane Proteins - metabolism / Messenger RNA / Metabolites / Mice / Models, Biological / non-specific protein-tyrosine kinase / Obesity / Peroxisome proliferator-activated receptors / Phosphorylation / Phosphorylation - drug effects / Protein Binding - drug effects / Proteins / Receptors / Retinaldehyde / Retinoic acid / Retinol binding proteins / retinol-binding protein / Retinol-Binding Proteins - metabolism / Signal transduction / Signal Transduction - drug effects / SOCS-3 protein / Stat5 protein / STAT5 Transcription Factor - metabolism / transcription (genetics) / Transcription factors / Transcriptional Activation - drug effects / Triglycerides - metabolism / Tyrosine / Vitamin A / Vitamin A - metabolism / White adipose tissue