title: Progressive endoplasmic reticulum stress contributes to hepatocarcinogenesis in fatty acyl-CoA oxidase 1-deficient mice.
abstract: Fatty acyl-coenzyme A oxidase 1 (ACOX1) knockout (ACOX1(-/-)) mice manifest hepatic metabolic derangements that lead to the development of steatohepatitis, hepatocellular regeneration, spontaneous peroxisome proliferation, and hepatocellular carcinomas. Deficiency of ACOX1 results in unmetabolized substrates of this enzyme that function as biological ligands for peroxisome proliferator-activated receptor-α (PPARα) in liver. Here we demonstrate that sustained activation of PPARα in ACOX1(-/-) mouse liver by these ACOX1 substrates results in endoplasmic reticulum (ER) stress. Overexpression of transcriptional regulator p8 and its ER stress-related effectors such as the pseudokinase tribbles homolog 3, activating transcription factor 4, and transcription factor CCAAT/-enhancer-binding protein homologous protein as well as phosphorylation of eukaryotic translation initiation factor 2α, indicate the induction of unfolded protein response signaling in the ACOX1(-/-) mouse liver. We also show here that, in the liver, p8 is a target for all three PPAR isoforms (-α, -β, and -γ), which interact with peroxisome proliferator response elements in p8 promoter. Sustained activation of p8 and unfolded protein response-associated ER stress in ACOX1(-/-) mouse liver contributes to hepatocyte apoptosis and liver cell proliferation culminating in the development of hepatocarcinogenesis. We also demonstrate that human ACOX1 transgene is functional in ACOX1(-/-) mice and effectively prevents metabolic dysfunctions that lead to ER stress and carcinogenic effects. Taken together, our data indicate that progressive PPARα- and p8-mediated ER stress contribute to the hepatocarcinogenesis in ACOX1(-/-) mice.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Huang
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.forename: Songtao
authors.initials: S
authors.lastname: Yu
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Liang
authors.initials: L
authors.lastname: Bai
authors.forename: Aurore
authors.initials: A
authors.lastname: Vluggens
authors.forename: Mustapha
authors.initials: M
authors.lastname: Cherkaoui-Malki
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: Jayme
authors.initials: J
authors.lastname: Borensztajn
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D042962:Acyl-CoA Oxidase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics*; D019076:Transgenes
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D047493:PPAR alpha; D042962:Acyl-CoA Oxidase