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Daniel D. Bikle, MD, PhD
VA Medical Center and University of California San Francisco
1700 Owens St., Rm 373
San Francisco, CA 94158 (USA)
E-Mail [email protected]
Giustina A, Bilezikian JP (eds): Vitamin D in Clinical Medicine.
Front Horm Res. Basel, Karger, 2018, vol 50, pp 31–41 (DOI: 10.1159/000486063)
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Tatiane Vilaçaa · Marise Lazaretti-Castrob
aAcademic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK; bDivision of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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Abstract
Vitamin D-binding protein (DBP) is the main transporter of vitamin D metabolites, initially described as a “group-specific component” (Gc-globulin). It is a multifunctional plasma protein, and besides its function in vitamin D metabolism, it also plays a major role in the clearance of G-actin monomers from plasma. DBP is a highly polymorphic protein, with a pattern of distribution very characteristic in the different ethnic groups, and its variants can present different affinities for vitamin D metabolites. Most of the 25-hydroxyvitamin D and its active form 1,25-dihydroxyvitamin D circulate bound to DBP (85–90%), and only less than 1% are free in the blood. DBP is produced mainly in the liver and can be influenced by many conditions, such as estrogen status, smoking, and malnutrition, which can have an effect on total vitamin D measurements. Recently, DBP has returned to the spotlight due to the discussion about its role in vitamin D physiology, which will be discussed in this chapter.
© 2018 S. Karger AG, Basel
Introduction
Vitamin D-binding protein (DBP) is known as the main transporter of vitamin D metabolites in the blood. DBP actions, however, go beyond vitamin D physiology. Peculiar characteristics and several functions of DBP make it an interesting molecule. The circulating concentration (5 × 10–6M) is remarkably higher than the main ligand, 25-hydroxyvitamin D (25[OH]D; 5 × 10–8M), suggesting that it might have other functions [1]. Besides acting as a vitamin D carrier, DPB has a major role in the clearance of G-actin monomers from plasma [2] and seems to directly regulate neutrophil, macrophage, and osteoclast activity [3, 4]. DBP deletion in humans has so far not been reported, suggesting that its absence may be lethal [1]. It is a highly polymorphic protein and multiple assays have been used to evaluate the concentration of DBP. The findings of discrepant results have given rise to many debates [5].
Recently, DBP has returned to the spotlight due to the discussion about its role in vitamin D physiology, which will be discussed in this chapter.
Structural Characteristics
Initially described in 1959 as a “group-specific component” (Gc-globulin) [6], DBP was renamed due to its role in vitamin D transport [7]. It is a multifunctional plasma protein that belongs to the albumin superfamily of binding proteins, which includes albumin (ALB), α-albumin, and α-fetoprotein (AFP) [8]. The DBP gene is located in the long arm of chromosome 4, at 4q11-q13, close to the ALB and AFP genes [9]. It is composed of 13 exons and 12 introns and results in a protein rich in cysteine residues, such as ALB and AFP [8]. These residues, in unique arrangements, allow the formation of disulfide bonds that gather the molecule into 3 distinct functional domains: 2 repeated homologous domains of 186 amino acids and a shorter one of 86 residues at the C-terminus [10]. The first domain includes the vitamin D-binding site (amino acids 35–49) and the cell-binding site while the second mediates a large number of other interactions. The third domain is similar to the first one, but it does not interact directly with vitamin D [11]. Another important region is the actin binding site, located between residues 373 and 403 [12]. The 3 domains form a 458-amino acid protein. Posttranslational modifications such as cleavage and glycosylation produce a protein with a molecular weight of approximately 58 kDa [10]. Different domain orientations and O-linked carbohydrate chains are important to establish the physiological functions of DBP [13].
DBP is produced mainly in the liver; however, the polymerase chain reaction has detected lower levels of the protein mRNA in the kidney, yolk sac, testis, and abdominal fat [14, 15]. DBP production is relatively stable through life and in vivo half-life is 2.5–3 days [13]. The protein has also been detected in the cerebrospinal fluid, seminal fluid, saliva, and breast milk.
DBP, free or bound, can be removed from plasma
