Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients.

Related collections

Most cited references 72

Record: found
Abstract: found
Article: not found

Liver fibrosis.

Ramón Bataller, David A. Brenner (2005)

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

0 comments Cited 1149 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Gene body methylation can alter gene expression and is a therapeutic target in cancer.

Xiaojing Yang, Han Han, Daniel De Carvalho … (2014)

DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression, yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC. Downregulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may, therefore, be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene overexpression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription. Copyright © 2014 Elsevier Inc. All rights reserved.

0 comments Cited 477 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Liver regeneration.

George Michalopoulos (2007)

Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.

0 comments Cited 426 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 21 May 2019

Publication date Collection: May 2019

Volume: 20

Issue: 10

Electronic Location Identifier: 2507

Affiliations

[1 ]Hepatology Program, CIMA, University of Navarra, 31180 Pamplona, Spain; mbarcena.1@ 123456alumni.unav.es (M.B.-V.); lcolyn@ 123456alumni.unav.es (L.C.)

[2 ]CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain

[3 ]Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31180 Pamplona, Spain

Author notes

[* ]Correspondence: magarfer@ 123456unav.es ;

Author information

Maite G. Fernandez-Barrena https://orcid.org/0000-0003-0375-6236

Article

Publisher ID: ijms-20-02507

DOI: 10.3390/ijms20102507

PMC ID: 6566358

PubMed ID: 31117267

SO-VID: e78cde1d-a645-4205-a04a-4af7f1e994ea

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis

Read this article at

Abstract

Related collections

Stress signalling in stem cells

Most cited references 72

Liver fibrosis.

Gene body methylation can alter gene expression and is a therapeutic target in cancer.

Liver regeneration.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 561

Cited by 25

Most referenced authors 1,421