Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Aurore Vluggens, Pierre Andreoletti, Navin Viswakarma, Yuzhi Jia, Kojiro Matsumoto, Wim Kulik, Mushfiquddin Khan, Jiansheng Huang, Dongsheng Guo, Sangtao Yu, Joy Sarkar, Inderjit Singh, M. Sambasiva Rao, Ronald J. Wanders, Janardan K. Reddy, Mustapha Cherkaoui-Malki*

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Disruption of the peroxisomal acyl-CoA oxidase 1 (Acox1) gene in the mouse results in the development of severe microvesicular hepatic steatosis and sustained activation of peroxisome proliferator-activated receptor-α (PPARα). These mice manifest spontaneous massive peroxisome proliferation in regenerating hepatocytes and eventually develop hepatocellular carcinomas. Human ACOX1, the first and rate-limiting enzyme of the peroxisomal Β-oxidation pathway, has two isoforms including ACOX1a and ACOX1b, transcribed from a single gene. As ACOX1a shows reduced activity toward palmitoyl-CoA as compared with ACOX1b, we used adenovirally driven ACOX1a and ACOX1b to investigate their efficacy in the reversal of hepatic phenotype in Acox1(-/-) mice. In this study, we show that human ACOX1b is markedly effective in reversing the ACOX1 null phenotype in the mouse. In addition, expression of human ACOX1b was found to restore the production of nervonic (24:1) acid and had a negative impact on the recruitment of coactivators to the PPARα-response unit, which suggests that nervonic acid might well be an endogenous PPARα antagonist, with nervonoyl-CoA probably being the active form of nervonic acid. In contrast, restoration of docosahexaenoic (22:6) acid level, a retinoid-X-receptor (RXRα) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRα and coactivators to the PPARα-response unit. The human ACOX1b isoform is more effective than the ACOX1a isoform in reversing the Acox1 null phenotype in the mouse. Substrate utilization differences between the two ACOX1 isoforms may explain the reason why ACOX1b is more effective in metabolizing PPARα ligands.

Original languageEnglish (US)
Pages (from-to)696-708
Number of pages13
JournalLaboratory Investigation
Volume90
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • Fatty acids oxidation
  • Hepatic steatosis
  • PPARα
  • Peroxisome proliferation
  • RXRα

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Vluggens, A., Andreoletti, P., Viswakarma, N., Jia, Y., Matsumoto, K., Kulik, W., Khan, M., Huang, J., Guo, D., Yu, S., Sarkar, J., Singh, I., Rao, M. S., Wanders, R. J., Reddy, J. K., & Cherkaoui-Malki, M. (2010). Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα. Laboratory Investigation, 90(5), 696-708. https://doi.org/10.1038/labinvest.2010.46