Acceleration of TAA-Induced Liver Fibrosis by Stress Exposure Is Associated with Upregulation of Nerve Growth Factor and Glycopattern Deviations.

Catalina Atorrasagasti,Sophia Borowski,Guillermo Mazzolini,María José Cantero,Irene Tirado-González,Flavia Piccioni,Juan Bayo,Nancy Freitag,Mariana G Garcia,Laura D Alaniz,Sandra M Blois

doi:10.3390/ijms22105055

Abstract

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased β1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.

Highlights

Liver fibrosis is a wound-healing response to acute or chronic cellular injury induced by viral hepatitis, alcohol, drugs, or metabolic diseases, among others
In order to analyze whether stress might be detrimental on liver fibrosis, TAA was chronically administered in mice with or without stress exposition
Stress stimulus was performed twice a week by exposition to sound stress for the duration of 24 h starting on week 2 of TAA administration, and liver fibrosis was evaluated in mice without stress (TAA)

Summary

Introduction

Liver fibrosis is a wound-healing response to acute or chronic cellular injury induced by viral hepatitis, alcohol, drugs, or metabolic diseases, among others. This process involves the production of several cytokines and chemokines like transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF), leading to the differentiation and 4.0/). Activated HSCs increase the synthesis of extracellular matrix components, and as a result, an excessive deposition of collagen types I and II, proteoglycans, and glycoproteins is observed in the liver parenchyma [1]. Chronic inflammation and cellular stress response developed during liver fibrosis may explain its close relationship with hepatocarcinogenesis [3]. Some clinical data suggested a correlation between psychosocial stress and the worsening of liver disease [9,10,11]

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Results

Conclusion