|Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes|
|Luo, Xiaoqin1,2,3; Xiao, Lei1; Yang, Haixia1,2,3; Zhang, Ruijuan2,3; Jiang, Manli1; Ni, Jiahua1; Lei, Ting1; Wang, Nanping1,4|
|关键词||Homocysteine Reactive oxygen species Heme Oxygenase-1 Nrf2 Bach1|
|刊名||NUTRITION & METABOLISM|
|WOS标题词||Science & Technology|
|类目[WOS]||Nutrition & Dietetics|
|研究领域[WOS]||Nutrition & Dietetics|
|关键词[WOS]||TRANSCRIPTION FACTOR NF-E2 ; LEUCINE-ZIPPER PROTEIN ; OXIDATIVE STRESS ; EPITHELIAL-CELLS ; REPRESSOR BACH1 ; UP-REGULATION ; INDUCTION ; NRF2 ; DISEASE ; MICE|
Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for liver diseases, such as fatty liver and hepatic fibrosis. However, the mechanisms underlying this pro-oxidative effect of homocysteine (Hcy) in hepatocytes remain largely unknown. Thus, we investigated the effect of Hcy on the gene expression of heme oxygenase-1 (HO-1), the primary rate-limiting enzyme in heme catabolism and a key anti-oxidant detoxification enzyme in maintaining cellular redox homeostasis.
Methods: In vivo, twenty male C57BL/6 mice at 8 weeks of age were randomly divided into two groups. One group was fed a chow diet (chow group; n = 10), the other group of mice was fed a methionine-supplemented diet (Met group, 1 mg kg(-1) day(-1) L-methionine in drinking water; n = 10) for 4 weeks. In vitro, HepG2 cells were stimulated with different doses of homocysteine (Hcy).
Results: Four weeks′ methionine supplementation caused a significant increase of plasma Hcy concentration and a decrease of HO-1 expression in the liver of C57BL/6 mice than mice received chow diet. Besides, SOD enzyme activities were impaired and the level of oxidative stress markers, such as malondialdehyde (MDA) were elevated in the liver from mice supplemented with methionine compared with control mice. In cultured hepatocytes, Hcy treatment reduced both the mRNA and protein levels of HO-1 dose-dependently. However, Hcy had no effect on the gene expression of Nrf2, the major transcriptional regulator of HO-1. Instead, Hcy induced the expression of Bach1, a transcriptional repressor of HO-1. In addition, Hcy stimulated the nuclear localization of Bach1 but prevented that of Nrf2. Furthermore, we found that knockdown of Bach1 attenuated the suppression of the HO-1 expression by Hcy.
Conclusions: Collectively, our results demonstrated that Bach1 plays an important role in Hcy-triggered ROS generations through inhibiting HO-1 expression, likely, resulting from the disturbed interplay between Bach1 and Nrf2.
|项目编号||81302426 ; 31430045 ; 81470373 ; 81220108005 ; 81300242 ; 2013 M540762|
|资助机构||National Natural Science Foundation of China ; China Postdoctoral Science Foundation|
|作者单位||1.Xi An Jiao Tong Univ, Cardiovasc Res Ctr, Sch Med, Xian 710061, Peoples R China|
2.Xi An Jiao Tong Univ, Sch Med, Dept Publ Hlth, Xian 710061, Peoples R China
3.Xi An Jiao Tong Univ, Nutr & Food Safety Engn Res Ctr Shaanxi Prov, Sch Med, Xian 710061, Peoples R China
4.Peking Univ, Inst Cardiovasc Sci, Beijing 100191, Peoples R China
|Luo, Xiaoqin,Xiao, Lei,Yang, Haixia,et al. Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes[J]. NUTRITION & METABOLISM,2014,11.|
|APA||Luo, Xiaoqin.,Xiao, Lei.,Yang, Haixia.,Zhang, Ruijuan.,Jiang, Manli.,...&Wang, Nanping.(2014).Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes.NUTRITION & METABOLISM,11.|
|MLA||Luo, Xiaoqin,et al."Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes".NUTRITION & METABOLISM 11(2014).|
|art%3A10.1186%2F1743（920KB）||期刊论文||作者接受稿||开放获取||CC BY-NC-SA||浏览 请求全文|