title: Upregulation of heme oxygenase-1 expression by dehydrodiconiferyl alcohol (DHCA) through the AMPK-Nrf2 dependent pathway.
abstract: Oxidative stress is induced by the accumulation of free radicals, resulting in an imbalanced cellular redox state, which has been implicated in a variety of human diseases. Dehydrodiconiferyl alcohol (DHCA), a lignan compound isolated from Cucurbita moschata, has previously been reported to contain anti-adipogenic and anti-lipogenic effects on 3T3-L1 cells and primary MEFs (Abraham and Kappas, 2008). In this study, it was tested whether DHCA could affect the expression of HO-1, using Raw264.7 mouse macrophage cell line. DHCA increased the protein and RNA levels of HO-1 and upregulated its promoter activity. Data from transient transfection assays indicated that ARE located in the E1 region of the HO-1 promoter are important in this DHCA-mediated induction of HO-1 expression. DHCA was also shown to enhance the nuclear translocation and binding of Nrf2 to the respective DNA sequences. The upregulation of HO-1 expression by DHCA was also observed in primary macrophages derived from wild type animals, but not in those from Nrf2 KO mice. Effects of DHCA on HO-1 and Nrf2 were reduced when cells were treated with an AMPK inhibitor, Compound C, but not by PI3K/Akt or MAPK inhibitors. Data from an experiment using a specific siRNA or chemical inhibitor for HO-1 suggested that the DHCA-mediated induction of the HO-1 protein could suppress the LPS-stimulated production of NO. Taken together, our data suggest that DHCA induces the expression of HO-1 by controlling its promoter activity through the AMPK-Nrf2 pathway, eventually leading to the reduction of NO production, and may thus have potential as an effective antioxidant.
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Junghun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: sunyoung@snu.ac.kr.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010636:Phenols; C080686:dehydrodiconiferyl alcohol; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ARE; DHCA; HO-1; Nrf2; Oxidative stress