Plasma amino acids imbalance in cirrhotic patients disturbs the tricarboxylic acid cycle of dendritic cell

Eiji Kakazu,Masashi Ninomiya,Tooru Shimosegawa,Yoshiyuki Ueno,Osamu Kimura,Takayuki Kogure,Yasuteru Kondo

doi:10.1038/srep03459

Abstract

An imbalance of plasma amino acids (AA) is observed cirrhotic patients. Here we report that the imbalance suppresses the maturation of dendritic cells (DCs) by reducing the intracellular ATP due to interference with the mitochondrial tricarboxylic acid (TCA) cycle. We used serum-free culture medium consistent with the average concentration of the plasma AA from a healthy volunteer (HCM) and that from patients with advanced cirrhosis (ACM). We compared the function of DCs and the metabolism of glucose-amino acids under each medium. The maturation and intracellular ATP of immature DCs were lower under ACM in spite of the enhancement of mitochondrial respiratory chain complex genes. Metabolomics revealed that the TCA cycle metabolite, fumarate and 2-oxoglutarate were increased in DCs generated under ACM. Consistent with in vitro, In CD1c+ or CD14+ cells from cirrhotic patients, the gene expression of 2-oxoglutarate-succinate-fumarate transition enzymes were significantly different from the cells of healthy controls.

Highlights

IntroductionWe report that the imbalance suppresses the maturation of dendritic cells (DCs) by reducing the intracellular ATP due to interference with the mitochondrial tricarboxylic acid (TCA) cycle
An imbalance of plasma amino acids (AA) is observed cirrhotic patients
After adding LPS, the mitochondrial membrane potential was significantly decreased under healthy control medium (HCM), Figure 1 | Amino acid concentrations similar to those in plasma of patients with advanced cirrhosis impaired the maturation of monocytederived dendritic cells (MoDCs)

Summary

Introduction

We report that the imbalance suppresses the maturation of dendritic cells (DCs) by reducing the intracellular ATP due to interference with the mitochondrial tricarboxylic acid (TCA) cycle. In patients with advanced cirrhosis, various metabolic disorders involving glucose, protein-amino acids, lipids, vitamins, and minerals, appear, because liver is the most important organ for maintaining nutritional homeostasis. Recent study reveals that malnutrition impairs interferon signaling through mTOR pathways in patients with chronic hepatitis C10, and we reported that the amino acids imbalance of patients with cirrhosis suppresses the maturation of DCs, accompanied by the down-regulation of the mTOR signal[3,11]. The aim of this study, was to investigate the influence of the extracellular amino acid imbalance observed in patients with cirrhosis on the function of DCs and the energy metabolism

Methods

Results

Conclusion