title: High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD).
abstract: 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.
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ge
authors.affiliation: Medical Research Council Centre for Drug Safety Science, Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Yongke
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Elena
authors.initials: E
authors.lastname: Arriazu
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Tung-Ming
authors.initials: TM
authors.lastname: Leung
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Arielle L
authors.initials: AL
authors.lastname: Klepper
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Branch
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029 and.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Division of Liver Diseases, Department of Medicine and Icahn School of Medicine at Mount Sinai, New York, New York 10029. Electronic address: natalia.nieto@mssm.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Nieto
mesh_terms: D000107:Acetylation; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation / Q000235:genetics; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational
chemical_list: D000975:Antioxidants; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D016877:Oxidants
keywords: Alcohol; Hepatocyte; High Mobility Group Box 1; Inflammation; Liver; Post-translational Modification (PTM)