Abstract
BackgroundIn sepsis, vitamin D binding protein (VDBP) has been shown to be low-expressed. The current study examined the relationship between serum VDBP level and liver injury in sepsis patients, as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide (LPS).MethodsThe human study included 78 sepsis patients and 50 healthy volunteers. Sepsis patients were categorized into sepsis survivor group (n = 43) and sepsis non-survivor group (n = 35) based on 28-day mortality for data analysis. Adult male C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Serum samples were collected on day 1, 3, 5 and 7 to determine the levels of VDBP, 25-hydroxyvitamin D [25(OH)D3], 1,25-dihydroxyvitamin D [1,25(OH)2D3], interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells.ResultsSerum levels of VDBP, 25(OH)D3, and 1,25(OH)2D3 were significantly lower in sepsis patients vs. the healthy control (P < 0.001), as well as in the sepsis non-survivor group vs. the sepsis survivor group (P < 0.001, P = 0.0338, or P = 0.0013, respectively). Lower serum VDBP level was associated with higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (r = − 0.2565, P = 0.0234) and Sequential Organ Failure Assessment score (r = − 0.3522, P = 0.0016), but lower serum albumin (ALB, r = 0.4628, P < 0.001) and total protein (TP, r = 0.263, P = 0.02). In CLP mice, there was a 5-day period of serum VDBP reduction, followed by return towards the baseline on day 7. VDBP was also decreased in LPS-treated THLE2 cells (P < 0.001). VDBP overexpression reduced LPS-induced THLE2 damage. Reduced damage was associated with decreased oxidative stress and inactivation of the c-Jun N-terminal kinase signaling pathway.ConclusionVDBP may be protective against sepsis-induced liver injury.
Highlights
Sepsis is a major health threat with an incidence of 45 per 10,000 people and approximately 20% mortality [1,2,3]
Serum vitamin D binding protein (VDBP), 25(OH)D3, and 1,25(OH)2D3 were lower in sepsis patients than healthy controls In comparison to the healthy control group, serum VDBP, 25(OH)D3, and 1,25(OH)2D3 levels were significantly lower in sepsis survivor group [VDBP: (418.06 ± 64.26) μg/ml vs. (295.20 ± 52.90) μg/ ml, P < 0.001; 25(OH)D3: (112.30 ± 23.70) nmol/L vs. (26.20 ± 12.70) nmol/L, P < 0.001; 1,25(OH)2D3: (21,706.50 ± 3331.60) fmol/L vs. (8106.00 ± 2952.10) fmol/L, P < 0.001] and sepsis non-survivor group [VDBP: (418.06 ± 64.26) vs. (178.10 ± 30.60) μg/ml, P < 0.001; 25(OH)D3: (112.30 ± 23.70) nmol/L vs. (19.60 ± 12.60) nmol/L, P < 0.001; 1,25(OH)2D3: (21,706.50 ± 3331.60) fmol/L vs. (5852.70 ± 1040.40) fmol/L, P < 0.001] (Fig. 1a–c)
Association of low VDBP level with disease severity and liver injury The severity of sepsis was assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assess‐ ment (SOFA) scores given their independent correlations with hospital mortality in sepsis patients [20, 23]
Summary
Sepsis is a major health threat with an incidence of 45 per 10,000 people and approximately 20% mortality [1,2,3]. Vitamin D binding protein (VDBP), known as Gc-globulin, is encoded by the group-specific component (GC) gene [9]. VDBP is essential for the binding, solubilization, and transport of vitamin D and metabolites, including 25-hydroxyvitamin D [25(OH)D3] (the major form in circulation) and 1,25-dihydroxyvitamin D [1,25(OH)2D3] (the active form) [10]. Previous studies showed lower VDBP plasma levels in sepsis patients than in healthy volunteers [10, 13]. Lower level of circulating VDBP in sepsis patients has been associated with more severe disease [14] and increased mortality [15]. Vitamin D binding protein (VDBP) has been shown to be low-expressed. The current study examined the relationship between serum VDBP level and liver injury in sepsis patients, as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide (LPS)
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