title: Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3.
abstract: OBJECTIVE
  Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade.
  
  
  METHODS
  Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA).
  
  
  RESULTS
  Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them.
  
  
  CONCLUSIONS
  These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.
authors: Population and Clinical Sciences Division, The Queensland Institute of Medical Research, Departments of Medicine, The University of Queensland, Australia. g.macdonald@medicine.herston.uq.edu.au
authors: G A
authors: GA
authors: MacDonald
authors: K R
authors: KR
authors: Bridle
authors: P J
authors: PJ
authors: Ward
authors: N I
authors: NI
authors: Walker
authors: K
authors: K
authors: Houglum
authors: D K
authors: DK
authors: George
authors: J L
authors: JL
authors: Smith
authors: L W
authors: LW
authors: Powell
authors: D H
authors: DH
authors: Crawford
authors: G A
authors: GA
authors: Ramm
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006680:HLA Antigens / Q000235:genetics; D006432:Hemochromatosis; D000071020:Hemochromatosis Protein; D022781:Hepatocytes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins; D008875:Middle Aged; D011347:Procollagen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011347:Procollagen; D016212:Transforming Growth Factor beta; D008315:Malondialdehyde; D007501:Iron