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The pathogenesis of Mallory body formation in ASH and NASH: The role of oxidative stress
Author(s) -
French Samuel W,
BardagGorce Fawzia,
French Barbara A,
Li Jun,
Amidi Fataneh,
Dedes Jennifer
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a190-a
Subject(s) - oxidative stress , epigenetics , acetylation , microbiology and biotechnology , histone deacetylase inhibitor , histone deacetylase , biology , chemistry , histone , biochemistry , gene
Mallory body formation was studied in vitro using mouse primary liver culture, and the human cell line HepG2 transfected with CYP2E1. Oxidative stress was imposed by pre‐conditioning HepG2 cells with arachidonic acid and iron, followed by ethanol. Signal transduction was studied using plasmid transfection, RNAi and inhibitors on liver cells derived from the drug‐primed mouse model of MB formation. Microarray of both in vitro models provided the functional pathways involved in MB formation. Human liver biopsies and liver from rats fed ethanol were used to document the involvement of the products of oxidative stress in NASH and ASH. MB formed in vitro beginning on days 2‐3 in mouse drug‐primed liver cell culture. MB‐like cytokeratin‐ubiquitin inclusions and aggresomes formed in HepG2‐CY2E1 over expressing hepatoma cells 48 hr after ethanol exposure after AA+Fe pre treatment. MBs in NASH and ASH shared the liver cell cytoplasm with 4HNE adduct aggresomes. M‐30 antibody to a CK‐18 fragment derived from activated caspase 3 digestion, colocalized in MBs. Microarray analysis of livers forming MBs, in vivo and in vitro showed a change in the expression of a large number of genes in an epigenetic manner. Up regulation of genes expressing proteins involved in histone acetylation and DNA methylation indicate that an epigenetic phenomenon was involved. Deacetylases were decreased and histone acetyltransferases were up regulated. Western blot analysis indicated an increase in acetylation of histone3 at lysine9. Supporting this, alcohol feeding increased histone 3 lysine 9 acetylation and p300 levels in the rat liver nuclear extracts in vivo.