Altered Metabolic Profile and Adipocyte Insulin Resistance Mark Severe Liver Fibrosis in Patients with Chronic Liver Disease

Melania Gaggini,Romina D’Aurizio,Ramy Younes,Elisabetta Bugianesi,Fabrizia Carli,Amalia Gastaldelli,Chiara Rosso

doi:10.3390/ijms20246333

Abstract

Metabolomics/lipidomics are important tools to identify novel biomarkers associated with liver damage. Patients with chronic liver disease (CLD) and hepatitis C virus (HCV) infection often have alterations in glucose, lipid and protein metabolism. The aim of this study was to evaluate if dysfunctional lipid and amino acid metabolism was associated with fibrosis severity and insulin resistance in CLD/HCV patients. We analyzed the baseline sera of 75 subjects with CLD/HCV infection HCV genotype-1, with proven liver biopsy prior to antiviral treatment. We measured amino acid (AA) and lipid concentration by gas and liquid chromatography-mass spectrometry respectively. Alterations in peripheral glucose metabolism due to insulin resistance (IR) were assesed by HOMA-IR (Glucose x Insulin/22.5), while adipose tissue IR was estimated as (Adipo-IR = Free Fatty Acids x Insulin). Baseline HOMA-IR and Adipo-IR were related to the degree of liver fibrosis. Reduction in ceramides 18:1/22:0, 18:1/24:0, diacylglycerol 42:6 and increased phosphocholine 40:6 were associated with higher fibrosis. Adipo-IR was related to lower levels of lysophosphatidylcholine 14:0 and 18:2 and with higher levels of sphingomyelin 18:2/24:0 and 18:2/24:1. Almost all AA were positively associated with Adipo-IR but not with HOMA-IR. We further confirmed the potential use of metabolomics and lipidomics in CLD/HCV subjects finding novel biomarkers of hepatic fibrosis and show that the adipose tissue IR is associated with more severe liver disease and is an important marker not only of altered lipid but also AA metabolism.

Highlights

Metabolomics and lipidomics are used to assess the metabolic factors involved in the onset of metabolic diseases, to understand the different metabolic pathways involved in organ damage [1,2]
We further confirmed the potential use of metabolomics and lipidomics in chronic liver disease (CLD)/hepatitis C virus (HCV) subjects finding novel biomarkers of hepatic fibrosis and show that the adipose tissue insulin resistance (IR) is associated with more severe liver disease and is an important marker of altered lipid and amino acid (AA) metabolism
Lipotoxicity is the result of increased peripheral lipolysis due to adipose tissue IR with overflow of free fatty acids to the liver that are in part stored as triglycerides or converted to lipotoxic species like ceramides [10], impaired suppression of lipolysis by insulin have been shown by some [11], but not others [4] in patients with HCV

Summary

Introduction

Metabolomics and lipidomics are used to assess the metabolic factors involved in the onset of metabolic diseases, to understand the different metabolic pathways involved in organ damage [1,2]. HCV infection might be able to disrupt glucose and lipid metabolism via up-regulation of TNF-alfa and/or down-regulation of suppressors of cytokine signaling and protein phosphatase 2A [6] that could be implicated in hepatic and extra-hepatic IR [4]. These metabolic derangements had been associated with the progression of liver fibrosis and significantly contributed to a decrease in sustained virological response rate [7] and might persist after completion of treatment. Previous studies in patients with NAFLD have associated increased adipose tissue IR to more severe liver fibrosis [12,13,14], and recently, Lim et al have confirmed these data in patients with CHC [11]

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