Biological Functions of RBP4 and Its Relevance for Human Diseases

Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body’s vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.

Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.