Adiponectin-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARα-dependent mechanism

Heng Lin, Chun Hsien Yu, Chih Yu Jen, Ching Feng Cheng, Ying Chou, Chih Cheng Chang, Shu Hui Juan

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Protective effects of adiponectin (APN; an adipocytokine) were shown against various oxidative challenges; however, its therapeutic implications and the mechanisms underlying hepatic iron overload remain unclear. Herein, we show that the deleterious effects of iron dextran on liver function and iron deposition were significantly reversed by adiponectin gene therapy, which was accompanied by AMP-activated protein kinase (AMPK) phosphorylation and heme oxygenase (HO)-1 induction. Furthermore, AMPK-mediated peroxisome proliferator-activated receptor-α (PPARα) activation by APN was ascribable to HO-1 induction. Additionally, we revealed direct transcriptional regulation of HO-1 by the binding of PPARα to a PPAR-responsive element (PPRE) by various experimental assessments. Interestingly, overexpression of HO-1 in hepatocytes mimicked the protective effect of APN in attenuating iron-mediated injury, whereas it was abolished by SnPP and small interfering HO-1. Furthermore, bilirubin, the end-product of the HO-1 reaction, but not CO, protected hepatocytes from iron dextran-mediated caspase activation. Herein, we demonstrate a novel functional PPRE in the promoter regions of HO-1, and APN-mediated HO-1 induction elicited an antiapoptotic effect and a decrease in iron deposition in hepatocytes subjected to iron challenge.

Original languageEnglish
Pages (from-to)1697-1709
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number4
DOIs
Publication statusPublished - Oct 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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