The effects of vitamin A, also known as retinol (ROH), are mediated by its active metabolites 11-cis-retinal, which mediates phototransduction, and retinoic acid, which activates gene transcription. ROH is transported through the circulation bound to serum retinol-binding protein (RBP). Uptake of ROH into cells occurs through the binding of RBP-ROH to the plasma membrane protein STRA6. High serum concentrations of RBP are associated with obesity and insulin resistance, but the mechanisms involved are unclear. Noting that the C terminus of STRA6 contains a Src homology 2 (SH2) domain–binding motif, Berry et al. examined the effects of recombinant RBP-ROH on STRA6 in transfected HepG2 hepatocarcinoma cells. RBP-ROH triggered the tyrosine phosphorylation of STRA6 but not of a mutant STRA6 lacking a tyrosine residue in the SH2 domain–binding motif. RBP-ROH stimulated the association of STRA6 with Janus-activated kinase 2 (JAK2), the phosphorylation of JAK2, and the phosphorylation of signal transducer and activator of transcription 5 (STAT5). None of these effects was stimulated by either RBP or ROH alone. Reporter assays showed that RBP-ROH–stimulated STAT5 was active, and RBP-ROH induced the expression of genes encoding suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator–activated receptor γ (PPARγ). In an adipocyte cell line, the RBP-ROH–STAT5 pathway stimulated the accumulation of triglycerides, which was mediated by PPARγ, and inhibited insulin receptor signaling, which was mediated by SOCS3. Injection of mice with RBP increased the extent of phosphorylation of STRA6, JAK2, and STAT5 in adipose tissue, induced the production of PPARγ, and inhibited the extent of insulin receptor phosphorylation in adipose tissue and muscle. Together, these data suggest that retinol regulates gene transcription independent of its metabolites and may explain the association of RBP with obesity and insulin resistance.
D. C. Berry, H. Jin, A. Majumdar, N. Noy, Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc. Natl. Acad. Sci. U.S.A. 108, 4340–4345 (2011). [Abstract] [Full Text]