Adiponectin-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARα dependent mechanism.
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.
Lin
Heng
H
Institute of Pharmacology and Toxicology, Tzu-Chi University, Hualien, Taiwan.
Yu
Chun-Hsien
CH
Jen
Chih-Yu
CY
Cheng
Ching-Feng
CF
Chou
Ying
Y
Chang
Chih-Cheng
CC
Juan
Shu-Hui
SH
D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006397:Hematinics / Q000633:toxicity; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology; D007505:Iron-Dextran Complex / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D052242:Adiponectin; D006397:Hematinics; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D007505:Iron-Dextran Complex; D051547:Heme Oxygenase-1