Plasma levels of apelin are reduced in patients with liver fibrosis and cirrhosis but are not correlated with circulating levels of bone morphogenetic protein 9 and 10

Abstract

Background: The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis.

Methods: Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA.

Results: Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with β-blockers.

Conclusions: Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.

Keywords: Apelin; Apelin receptor; BMP10; BMP9; Fibrosis; Liver cirrhosis; Liver disease.

Fig. 1

Apelin plasma levels compared in controls (n = 25) and patients with fibrosis (n = 14) or cirrhosis (n = 56). Mann Whitney test, ***p < 0.0001 indiates significant difference from control group. Horizontal bars show the median and interquartile range.

Fig. 2

Circulating apelin levels in patients with cirrhosis do not correlate with circulating BMP9 (A), pBMP10 levels (B), age (C), and liver disease severity scores (F, G, and H). In patients with cirrhosis, there are no differences in circulating apelin levels between males and females (D) and those on or off beta-blockers (E). Fig. 2A, B, C, F, G, and H: Spearman non-parametric correlation. Fig. 2D and H: Mann Whitney Test. Error bars show the median and interquartile range. Abbreviations: CPS – Child Pugh Score, MELD-Na – Model for End-stage Liver Disease incorporating sodium values, UKELD – United Kingdom model for End-stage Liver Disease. Individual levels of BMP9 and BMP10 (as pBMP10) have previously been published by us [23].