High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)

Growing clinical and experimental evidence suggests that sterile inflammation contributes to alcoholic liver disease (ALD). High mobility group box-1 (HMGB1) is highly induced during liver injury; however, a link between this alarmin and ALD has not been established. Thus, the aim of this work was t...

Descripción completa

Detalles Bibliográficos
Autores principales: Ge, Xiaodong, Antoine, Daniel J., Lu, Yongke, Arriazu, Elena, Leung, Tung-Ming, Klepper, Arielle L., Branch, Andrea D., Fiel, Maria Isabel, Nieto, Natalia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132775/
https://www.ncbi.nlm.nih.gov/pubmed/24928512
http://dx.doi.org/10.1074/jbc.M114.552141
_version_ 1782330675776454656
author Ge, Xiaodong
Antoine, Daniel J.
Lu, Yongke
Arriazu, Elena
Leung, Tung-Ming
Klepper, Arielle L.
Branch, Andrea D.
Fiel, Maria Isabel
Nieto, Natalia
author_facet Ge, Xiaodong
Antoine, Daniel J.
Lu, Yongke
Arriazu, Elena
Leung, Tung-Ming
Klepper, Arielle L.
Branch, Andrea D.
Fiel, Maria Isabel
Nieto, Natalia
author_sort Ge, Xiaodong
collection PubMed
description Growing clinical and experimental evidence suggests that sterile inflammation contributes to alcoholic liver disease (ALD). High mobility group box-1 (HMGB1) is highly induced during liver injury; however, a link between this alarmin and ALD has not been established. Thus, the aim of this work was to determine whether HMGB1 contributes to the pathogenesis of ALD. Liver biopsies from patients with ALD showed a robust increase in HMGB1 expression and translocation, which correlated with disease stage, compared with healthy explants. Similar findings were observed in chronic ethanol-fed wild-type (WT) mice. Using primary cell culture, we validated the ability of hepatocytes from ethanol-fed mice to secrete a large amount of HMGB1. Secretion was time- and dose-dependent and responsive to prooxidants and antioxidants. Selective ablation of Hmgb1 in hepatocytes protected mice from alcohol-induced liver injury due to increased carnitine palmitoyltransferase-1, phosphorylated 5′AMP-activated protein kinase-α, and phosphorylated peroxisome proliferator-activated receptor-α expression along with elevated LDL plus VLDL export. Native and post-translationally modified HMGB1 were detected in humans and mice with ALD. In liver and serum from control mice and in serum from healthy volunteers, the lysine residues within the peptides containing nuclear localization signals (NLSs) 1 and 2 were non-acetylated, and all cysteine residues were reduced. However, in livers from ethanol-fed mice, in addition to all thiol/non-acetylated isoforms of HMGB1, we observed acetylated NLS1 and NLS2, a unique phosphorylation site in serine 35, and an increase in oxidation of HMGB1 to the disulfide isoform. In serum from ethanol-fed mice and from patients with ALD, there was disulfide-bonded hyperacetylated HMGB1, disulfide-bonded non-acetylated HMGB1, and HMGB1 phosphorylated in serine 35. Hepatocytes appeared to be a major source of these HMGB1 isoforms. Thus, hepatocyte HMGB1 participates in the pathogenesis of ALD and undergoes post-translational modifications (PTMs) that could condition its toxic effects.
format Online
Article
Text
id pubmed-4132775
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-41327752014-08-19 High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD) Ge, Xiaodong Antoine, Daniel J. Lu, Yongke Arriazu, Elena Leung, Tung-Ming Klepper, Arielle L. Branch, Andrea D. Fiel, Maria Isabel Nieto, Natalia J Biol Chem Molecular Bases of Disease Growing clinical and experimental evidence suggests that sterile inflammation contributes to alcoholic liver disease (ALD). High mobility group box-1 (HMGB1) is highly induced during liver injury; however, a link between this alarmin and ALD has not been established. Thus, the aim of this work was to determine whether HMGB1 contributes to the pathogenesis of ALD. Liver biopsies from patients with ALD showed a robust increase in HMGB1 expression and translocation, which correlated with disease stage, compared with healthy explants. Similar findings were observed in chronic ethanol-fed wild-type (WT) mice. Using primary cell culture, we validated the ability of hepatocytes from ethanol-fed mice to secrete a large amount of HMGB1. Secretion was time- and dose-dependent and responsive to prooxidants and antioxidants. Selective ablation of Hmgb1 in hepatocytes protected mice from alcohol-induced liver injury due to increased carnitine palmitoyltransferase-1, phosphorylated 5′AMP-activated protein kinase-α, and phosphorylated peroxisome proliferator-activated receptor-α expression along with elevated LDL plus VLDL export. Native and post-translationally modified HMGB1 were detected in humans and mice with ALD. In liver and serum from control mice and in serum from healthy volunteers, the lysine residues within the peptides containing nuclear localization signals (NLSs) 1 and 2 were non-acetylated, and all cysteine residues were reduced. However, in livers from ethanol-fed mice, in addition to all thiol/non-acetylated isoforms of HMGB1, we observed acetylated NLS1 and NLS2, a unique phosphorylation site in serine 35, and an increase in oxidation of HMGB1 to the disulfide isoform. In serum from ethanol-fed mice and from patients with ALD, there was disulfide-bonded hyperacetylated HMGB1, disulfide-bonded non-acetylated HMGB1, and HMGB1 phosphorylated in serine 35. Hepatocytes appeared to be a major source of these HMGB1 isoforms. Thus, hepatocyte HMGB1 participates in the pathogenesis of ALD and undergoes post-translational modifications (PTMs) that could condition its toxic effects. American Society for Biochemistry and Molecular Biology 2014-08-15 2014-06-13 /pmc/articles/PMC4132775/ /pubmed/24928512 http://dx.doi.org/10.1074/jbc.M114.552141 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Molecular Bases of Disease
Ge, Xiaodong
Antoine, Daniel J.
Lu, Yongke
Arriazu, Elena
Leung, Tung-Ming
Klepper, Arielle L.
Branch, Andrea D.
Fiel, Maria Isabel
Nieto, Natalia
High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title_full High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title_fullStr High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title_full_unstemmed High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title_short High Mobility Group Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD)
title_sort high mobility group box-1 (hmgb1) participates in the pathogenesis of alcoholic liver disease (ald)
topic Molecular Bases of Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132775/
https://www.ncbi.nlm.nih.gov/pubmed/24928512
http://dx.doi.org/10.1074/jbc.M114.552141
work_keys_str_mv AT gexiaodong highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT antoinedanielj highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT luyongke highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT arriazuelena highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT leungtungming highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT klepperariellel highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT branchandread highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT fielmariaisabel highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald
AT nietonatalia highmobilitygroupbox1hmgb1participatesinthepathogenesisofalcoholicliverdiseaseald