title: Food-derived peroxidized fatty acids may trigger hepatic inflammation: a novel hypothesis to explain steatohepatitis.
abstract: OBJECTIVE
  Obesity and hepatic steatosis are frequently associated with the development of a non-alcoholic steatohepatitis (NASH). The mechanisms driving progression of a non-inflamed steatosis to NASH are largely unknown. Here, we investigated whether ingestion of peroxidized lipids, as being present in Western style diet, triggers the development of hepatic inflammation.
  
  
  METHODS
  Corn oil containing peroxidized fatty acids was administered to rats by gavage for 6 days. In a separate approach, hepatocytes (HC), endothelial (EC) and Kupffer cells (KC) were isolated from untreated livers, cultured, and incubated with peroxidized linoleic acid (LOOH; linoleic acid (LH) being the main fatty acid in corn oil). Samples obtained from in vivo and in vitro studies were mainly investigated by qRT-PCR and biochemical determinations of lipid peroxidation products.
  
  
  RESULTS
  Rat treatment with peroxidized corn oil resulted in increased hepatic lipid peroxidation, upregulation of nitric oxide synthetase-2 (NOS-2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα), elevation of total nitric oxides, and increase in cd68-, cd163-, TNFα-, and/or COX-2 positive immune cells in the liver. When investigating liver cell types, LOOH elevated the secretion of TNFα, p38MAPK phosphorylation, and mRNA levels of NOS-2, COX-2, and TNFα, mainly in KC. The elevation of gene expression could be abrogated by inhibiting p38MAPK, which indicates that p38MAPK activation is involved in the pro-inflammatory effects of LOOH.
  
  
  CONCLUSIONS
  These data show for the first time that ingestion of peroxidized fatty acids carries a considerable pro-inflammatory stimulus into the body which reaches the liver and may trigger the development of hepatic inflammation.
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Therese
authors.initials: T
authors.lastname: Böhm
authors.forename: Heidi
authors.initials: H
authors.lastname: Berger
authors.forename: Marzieh
authors.initials: M
authors.lastname: Nejabat
authors.forename: Teresa
authors.initials: T
authors.lastname: Riegler
authors.forename: Florian
authors.initials: F
authors.lastname: Kellner
authors.forename: Mario
authors.initials: M
authors.lastname: Kuttke
authors.forename: Sandra
authors.initials: S
authors.lastname: Sagmeister
authors.forename: Monika
authors.initials: M
authors.lastname: Bazanella
authors.forename: Klaus
authors.initials: K
authors.lastname: Stolze
authors.forename: Anahita
authors.initials: A
authors.lastname: Daryabeigi
authors.forename: Nora
authors.initials: N
authors.lastname: Bintner
authors.forename: Michael
authors.initials: M
authors.lastname: Murkovic
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wagner
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
authors.forename: Nataliya
authors.initials: N
authors.lastname: Rohr-Udilova
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
mesh_terms: D000818:Animals; D003314:Corn Oil / Q000009:adverse effects / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000009:adverse effects* / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000009:adverse effects* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D018836:Inflammation Mediators; D008054:Lipid Peroxides; D003314:Corn Oil
keywords: COX-2; EC; HC; IL-1β; IL6; KC; Kupffer cells; LH; LOOH; Lipid peroxidation; NASH; NO-synthetase 2; NOS-2; NPC; OIL; PO; RNS; ROS; TNFα; WA; Western style diet; cyclooxygenase-2; endothelial cells; hepatocytes; interleukin-1β; interleukin-6; linoleic acid; native corn oil; non-ethanol-induced steatohepatitis; non-parenchymal liver cells; peroxidized corn oil; peroxidized linoleic acid; reactive nitrogen species; reactive oxygen species; tumor necrosis factor α; water