title: Aging modulates susceptibility to mouse liver Mallory-Denk body formation.
abstract: Mallory-Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions found in several liver diseases and consist primarily of the cytoskeletal proteins, keratins 8 and 18 (K8/K18). Recent evidence indicates that the extent of stress-induced protein misfolding, a K8>K18 overexpression state, and transglutaminase-2 activation promote MDB formation. In addition, the genetic background and gender play an important role in mouse MDB formation, but the effect of aging on this process is unknown. Given that oxidative stress increases with aging, the authors hypothesized that aging predisposes to MDB formation. They used an established mouse MDB model-namely, feeding non-transgenic male FVB/N mice (1, 3, and 8 months old) with 3,5 diethoxycarbonyl-1,4-dihydrocollidine for 2 months. MDB formation was assessed using immunofluorescence staining and biochemically by demonstrating keratin and ubiquitin-containing crosslinks generated by transglutaminase-2. Immunofluorescence staining showed that old mice had a significant increase in MDB formation compared with young mice. MDB formation paralleled the generation of high molecular weight ubiquitinated keratin-containing complexes and induction of p62. Old mouse livers had increased oxidative stress. In addition, 20S proteasome activity and autophagy were decreased, and endoplasmic reticulum stress was increased in older livers. Therefore, aging predisposes to experimental MDB formation, possibly by decreased activity of protein degradation machinery.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. hanadas@med.kurume-u.ac.jp
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hanada
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.forename: Jun
authors.initials: J
authors.lastname: Akiba
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Raymond
authors.initials: R
authors.lastname: Kwan
authors.forename: Eitaro
authors.initials: E
authors.lastname: Taniguchi
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nagata
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D059865:Endoplasmic Reticulum Stress; D005455:Fluorescent Antibody Technique; D006984:Hypertrophy; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059609:Mallory Bodies / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis
chemical_list: D046988:Proteasome Endopeptidase Complex