Renal function is a major predictor of circulating acyl-CoA-binding protein/diazepam-binding inhibitor

Abstract

Objective: Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.

Design/methods: Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.

Results: Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized β=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mACBP mRNA expression in different tissues of CKD mice in vivo or in indoxyl sulfate-treated adipocytes in vitro.

Conclusions: Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.

Keywords: Acyl-CoA-binding protein; adipokines; chronic kidney disease; diabetic kidney disease; diazepam binding inhibitor; hemodialysis; type 2 diabetes mellitus.

Figure 1

ACBP serum concentrations before and after HD as well as before and after unilateral nephrectomy in matched samples of patients. ACBP serum concentrations were measured before and immediately after hemodialysis (HD) in 10 subjects from study population 1 in (A) and before, as well as within 30 hours after, partial or total unilateral nephrectomy in 20 subjects from study population 2 in (B). Each data point refers to one patient. P-values were calculated by Wilcoxon signed-rank test. ** indicates p < 0.01, ***p < 0.001.

Figure 2

mACBP mRNA expression in a mouse model of diabetic kidney disease compared to control mice. In all experiments, mice with 24 weeks of age with severe diabetic kidney disease (DKD) (eNOS^-/-; db/db; black bars) were compared to obese, diabetic (db/db; dark grey bars), lean, endothelial dysfunctional (eNOS^-/- mice; light grey bars), as well as healthy, lean control mice (db/+ mice; white bars). (A–F) mACBP mRNA expression normalized to m36B4 in (A) brown adipose tissue (BAT), (B) subcutaneous adipose tissue (SAT), (C) visceral adipose tissue (VAT), (D) kidney, (E) liver, and (F) hypothalamus. Results are displayed as means ± standard deviation. p-values were calculated by one-way ANOVA including Bonferroni adjustment for post-hoc tests. N ≥ 5 per group. *indicates p < 0.05, **p < 0.01, ****p<0.0001 for subgroup comparisons.

Figure 3

mACBP mRNA expression after treatment in 3T3-L1 white adipocytes and brown adipocytes with uremic toxin indoxyl sulfate. mACBP mRNA expression in (A) murine 3T3-L1 white adipocytes, and (B) differentiated, immortalized murine brown adipocytes after 24 hours-lasting incubation with 1 mM indoxyl sulfate and control cells exposed to 1 mM potassium sulfate for 24 hours. The mACBP mRNA expression is shown as normalized to m36B4. Results are displayed as means ± standard deviation. p-values were calculated by Student’s t test. N ≥ 5 per group.