Progressive endoplasmic reticulum stress contributes to hepatocarcinogenesis in fatty acyl-CoA oxidase 1-deficient mice

Jiansheng Huang, Navin Viswakarma, Songtao Yu, Yuzhi Jia, Liang Bai, Aurore Vluggens, Mustapha Cherkaoui-Malki, Mushfiquddin Khan, Inderjit Singh, Gongshe Yang, M. Sambasiva Rao, Jayme Borensztajn, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

44 Scopus citations

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 receptorα (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 stressrelated 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 responseassociated 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.

Original languageEnglish (US)
Pages (from-to)703-713
Number of pages11
JournalAmerican Journal of Pathology
Volume179
Issue number2
DOIs
StatePublished - Aug 1 2011

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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