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

研究成果: 雜誌貢獻文章

39 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)1697-1709
頁數13
期刊American Journal of Pathology
177
發行號4
DOIs
出版狀態已發佈 - 十月 2010

指紋

Peroxisome Proliferator-Activated Receptors
Heme Oxygenase-1
Adiponectin
Iron
Liver
Wounds and Injuries
Hepatocytes
AMP-Activated Protein Kinases
Dextrans
Adipokines
Iron Overload
Carbon Monoxide
Caspases
Bilirubin
Genetic Promoter Regions
Genetic Therapy
Phosphorylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

引用此文

Adiponectin-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARα-dependent mechanism. / Lin, Heng; Yu, Chun Hsien; Jen, Chih Yu; Cheng, Ching Feng; Chou, Ying; Chang, Chih Cheng; Juan, Shu Hui.

於: American Journal of Pathology, 卷 177, 編號 4, 10.2010, p. 1697-1709.

研究成果: 雜誌貢獻文章

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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.",
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AU - Chang, Chih Cheng

AU - Juan, Shu Hui

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