Adipocyte Fatty-Acid Binding Protein is Overexpressed in Cirrhosis and Correlates with Clinical Outcomes

Isabel Graupera,Mar Coll,Càndid Villanueva,Cristina Solé,Rebeca Moreira,Manuel Morales-Ruiz,Núria Fabrellas,Elisa Pose,Pere Ginès,Adrià Juanola,Chiara Elia,Delia Blaya,Gloria De Prada,Salvatore Piano,Elsa Solà,Patricia Huelin,Pau Sancho-Bru

doi:10.1038/s41598-017-01709-0

Abstract

Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17–39) vs 10 (9–17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5–2.1) vs 0.6 (0.4–1) ng/mL p = 0.04 and A-FABP4: 37 (20–68) vs 16 (11–33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis.

Highlights

Abundant in the liver but is expressed in intestine, pancreas, kidney, lung, and stomach
L-FABP1 plasma levels are increased in patients with acute rejection after liver transplantation[5]; plasma levels of Intestinal fatty-acid binding protein 2 (I-FABP2) are increased in intestinal ischemia and are a marker of intestinal epithelium damage and sepsis of abdominal origin[6, 7]; heart and brain Fatty-acid-binding proteins (FABPs) (H-FABP3 and B-FABP7) are released into the circulation immediately after cardiac or brain cell damage[4]; plasma A-FABP4 levels are increased in several metabolic and cardiovascular conditions and have been shown to predict long-term cardiovascular events[3, 8, 9]
The results of the current study show that the plasma levels of three different FABPs, A-FABP4, L-FABP1, and I-FABP2, are increased in decompensated cirrhosis with respect to those of healthy subjects and correlate with important disease outcomes

Summary

Introduction

Abundant in the liver but is expressed in intestine, pancreas, kidney, lung, and stomach. Hepatic gene expression of L-FABP1 has been shown to be down-regulated in non-alcoholic fatty liver disease (NAFLD)[15] and A-FABP4 plasma levels have been associated with liver inflammation in NAFLD patients[16]. Because advanced cirrhosis is characterized by abnormalities in different organs (liver, intestine, kidney, immune system...), we hypothesized that cirrhosis could be associated with alterations in FABPs plasma levels that could correlate with complications and disease outcomes. On this background, the aim of the present study was to investigate FABPs plasma levels and hepatic gene expression in decompensated cirrhosis and assess the relationship between FABPs and outcomes in cirrhosis. We studied three FABPs because of their potential pathogenic interest in cirrhosis: L-FABP-1 and I-FABP2 because of their role in liver and intestinal damage and A-FABP4 because of its relationship with systemic inflammation and immune system

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