title: Alleviation mechanisms against hepatocyte oxidative stress in patients with chronic hepatic disorders.
abstract: OBJECTIVE
  Autophagy induction and Mallory-Denk body (MDB) formation have been considered to have cytoprotective effects from cellular stress in liver diseases. We investigated the relations among oxidative stress, autophagy and MDB formation in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) to clarify the alleviation mechanisms against oxidative stress of hepatocytes.
  
  
  METHODS
  First, we treated cultured cells with proteasome inhibitor (PI) or free fatty acid (FFA) and evaluated endoplasmic reticulum (ER) stress, oxidative stress, ubiquitinated proteins and p62 by western blotting. Then, we used human liver biopsy samples to evaluate oxidative stress, autophagy and MDB formation by immunohistochemical analysis.
  
  
  RESULTS
  Treatment with PI or FFA increased ER stress, oxidative stress, ubiquitinated proteins and p62 in cultured cells. Human liver biopsy samples of CHC and NAFLD showed that MDB formed in areas with strong oxidative stress and that the MDB-containing cells circumvented oxidative stress. Keratin 8 (K8) expression was strong in MDB-containing cells in CHC and NAFLD. However, in CHB samples, the expression of K8 was not increased in response to oxidative stress and MDB aggregates did not appear. Aminotransferase values were significantly lower in patients with CHC and NAFLD in whom light chain 3 antibody expression was increased in response to oxidative stress.
  
  
  CONCLUSIONS
  Strong expression of K8 was considered to be important for MDB formation. MDB protect liver cells from oxidative stress at a cellular level and autophagy reduced hepatic damage when it was induced in the hepatocytes exposed to strong oxidative stress.
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hiura
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Honma
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Miyagawa
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oe
authors.affiliation: Department of Pathology and Cell Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mihara
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Oe
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Sato-Morita
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Katsuki
authors.affiliation: Third Department of Internal Medicine, Kitakyushu, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
keywords: Mallory-Denk body; autophagy; chronic viral hepatitis; non-alcoholic fatty liver disease; oxidative stress