Vitamin D Binding Protein: A Historic Overview

Abstract

Vitamin D and all its metabolites are bound to a specific vitamin D binding protein, DBP. This protein was originally first discovered by its worldwide polymorphism and called Group-specific Component (GC). We now know that DBP and GC are the same protein and appeared early in the evolution of vertebrates. DBP is genetically the oldest member of the albuminoid family (including albumin, α-fetoprotein and afamin, all involved in transport of fatty acids or hormones). DBP has a single binding site for all vitamin D metabolites and has a high affinity for 25OHD and 1,25(OH)2D, thereby creating a large pool of circulating 25OHD, which prevents rapid vitamin D deficiency. DBP of higher vertebrates (not amphibians or reptiles) binds with very high affinity actin, thereby preventing the formation of polymeric actin fibrils in the circulation after tissue damage. Megalin is a cargo receptor and is together with cubilin needed to reabsorb DBP or the DBP-25OHD complex, thereby preventing the urinary loss of these proteins and 25OHD. The total concentrations of 25OHD and 1,25(OH)2D in DBP null mice or humans are extremely low but calcium and bone homeostasis remain normal. This is the strongest argument for claiming that the "free hormone hypothesis" also applies to the vitamin D hormone, 1,25(OH)2D. DBP also transports fatty acids, and can play a role in the immune system. DBP is genetically very polymorphic with three frequent alleles (DBP/GC 1f, 1s, and 2) but in total more than 120 different variants but its health consequences, if any, are not understood. A standardization of DBP assays is essential to further explore the role of DBP in physiology and diseases.

An Update on Vitamin D Metabolism

“…Transport of vitamin D metabolites is accounted for 85% by vitamin D binding protein (DBP) with high affinity and 15% by albumin with low affinity [72].…”

“…Summarizing recent evidences, DBP functions as a large pool reservoir of circulating 25OHD, which prevents for vitamin D deficiency when supply is low. Moreover, DBP also functions as a regulator for vitamin D access to cells in kidney and most likely in the other peripheral tissues [72].…”

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design

“…Once produced, vitamin D 3 can be released from the epidermal’ plasma membranes reaching the circulation system bound to the vitamin D binding protein (VDBP or simply DBP) [ 19 , 20 , 21 ], a member of the albuminoid superfamily produced in the liver [ 14 , 22 ]. Like albumin, DBP is a constitutive protein, able to transport vitamin D, whether produced in the skin or ingested, to the liver and kidneys [ 23 ], where it undergoes two sequential hydroxylation reactions, finally providing the biologically active metabolite.…”

Vitamin D Metabolism Revised: Fall of Dogmas

“…DBP in serum can be measured by mono-and polyclonal antibodies and more recently also by mass spectroscopy, whereby careful attention must be given to assure equal measurements of all isoforms of DBP. (108) DBP concentrations are markedly decreased in liver diseases, nephrotic syndrome, and in patients with very severe acute illness or acute trauma due at least in part to its actin scavenging function. (109) Therefore, DBP is not a passive but an active player in the overall vitamin D homeostasis and is probably under control of various metabolic signals (Fig.…”