Vitamin D in Clinical Medicine. Группа авторов

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СКАЧАТЬ circulates in the bloodstream at higher levels than vitamin D metabolites and less than 5% of the protein’s sterol binding sites are occupied [1, 12]. The molar excess suggests that DBP could act as a protective mechanism against vitamin D toxicity, but also that the protein is involved in other physiological functions.

      Other DBP Functions

      Actin Scavenger System

      Actin is an important cytoskeletal protein, highly conserved in eukaryotic cells. Two main forms of the protein are described, a monomeric globular form (G-actin) and a linear polymeric form called F-actin. Once in the extracellular compartment, actin polymerizes in the filamentary form [2]. The polymer may cause coagulation cascade activation, vascular obstruction, and cellular dysfunction. Actin is released by tissue injury and cell death, and DBP is able to bind to it with high affinity and to prevent filament formation [18]. In conjunction with gelsolin, another serum protein, DBP forms an actin scavenger system. It is able to rapidly sequester free actin from circulation, and the major DBP polymorphisms have equal binding affinity. It is possible that the molar excess of the protein is related to this function [2].

      Fatty Acid Transport

      All the members of the albumin superfamily of binding proteins are able to transport free fatty acids (FFA). ALB has several low- and high-affinity binding sites for FFA, while DBP has a single high-affinity binding site. ALB is also much more abundant in the plasma, which results in DBP having only a contributory role. The binding of unsaturated FFA reduces DBP affinity for vitamin D metabolites, but this effect is not observed for saturated FFA [17]. These variations are a result of the specific conformational changes induced for each FFA in DBP [2].

      DBP-Macrophage Activation Factor

DBP can be deglycosylated by T- and B-cell glycosidases and act as a macrophage activation factor (MAF), which is called DBP-MAF [17]. This activity was discovered when mouse peritoneal cells were stimulated with lysophosphatidylcholine, and it resulted in an increase in phagocytic activity [20]. Analysis revealed that this increase was associated with the deglycosylation of DBP by β-galactosidase and sialidase of the B and T cells, resulting in DBP-MAF. The different isoforms of DBP show variable susceptibility to deglycosylation. This feature could explain the association of the isoforms with diseases like chronic obstructive pulmonary disease, bronchiectasis, and tuberculosis [17].

      Chemotaxis

      Chemotaxis is an important process of neutrophil recruitment during inflammation. DBP has no intrinsic chemotactic effect; however, when bound to complement component 5a (C5a), it enhances C5a-mediated neutrophil and macrophage chemotaxis [17]. The action requires binding to cell surface receptor, which is mediated by the residues 130–149 in the protein [12]. Interestingly, binding to vitamin D metabolites (25[OH]D or 1,25[OH]₂D) reduces DBP chemotactic action due to binding site competition [2]. The 3 major polymorphisms (GC1F, GC1S, and GC2) have comparable chemotactic activity.

      DBP Serum Concentrations

The relative abundance of DBP in serum permits the use of simple immunochemical techniques for measurements. Radioimmunoassay, rocket immune electrophoresis, single radial immunodiffusion, turbidimetry, nephelometry, and ELISA have been used [2]. Normal DBP levels can vary according to the used biochemical methodology but usually range from 200 to 600 mg/L in healthy subjects [21, 22]. There is no season-, weight-, or age-related variance of DBP levels [12, 23] but a circadian rhythm of DBP serum concentrations has been observed, with lower levels in the morning, followed by a rapid increase until reaching a plateau during the day [18]. The correction of vitamin D deficiency by supplementation does not change DBP levels [24]. The serum concentrations are lower in men than women, possibly due to the estrogen effect on its synthesis [23–25]. Furthermore, a hormonal contraceptive is associated with 13–25% higher concentrations of DBP, but, apparently, there are no differences in free hormone levels [26].

Decreased DBP levels are found in advanced liver disease (decreased production) [27], nephrotic syndrome, and diabetes mellitus with nephropathy (probably due to urinary loss). DBP is filtered through the glomerulus and in normal conditions, is reabsorbed by megalin-mediated endocytosis and catabolized by proximal tubule epithelial cells, reducing the urinary excretion to trace amounts. Acute tubular necrosis and glomerulonephropathies can disturb this process and DBP can be found in urine, as an early biomarker for kidney injury [28]. Lower levels of DBP were also found in inflammatory states, like acute injury or sepsis [29]. Compared to controls, individuals with musculoskeletal inflammatory disorders also showed lower levels of DBP, measured by two-dimensional gel electrophoresis. The reasons for the connection between inflammatory states and decreased DBP levels are still unknown, but it may be speculated that DBP, as a precursor for MAF, could be consumed by the increased formation of MAF and ensuing activation of macrophages and neutrophils at inflammation sites [30].

      DPB and Vitamin D Deficiency

Vitamin D deficiency has been described worldwide, defined by 25(OH)D levels, and there is a large discussion about the adequate threshold [31, 32]. Furthermore, the circulating levels of 25(OH)D are strongly related to the amount of the carrier protein, which might be influenced by multiple conditions, as discussed above [33]. In addition, the affinity for the ligand varies between the different polymorphisms, and the relevance of all these aspects in the vitamin D physiology is still being debated. Among the DBP phenotypes, the carriers of the Gc1F allele in homozygosis are more prone to have lower levels of 25(OH)D.

The free hormone СКАЧАТЬ