Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes

Nutrition & Metabolism

Nanping Wang¹  Ting Lei²  Jiahua Ni²  Manli Jiang²  Ruijuan Zhang³  Haixia Yang³  Lei Xiao²  Xiaoqin Luo³ 

[1] Institute of Cardiovascular Science, Peking University, Beijing 100191, China;Cardiovascular Research Center, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China;Nutrition and Food Safety Engineering Research Center of Shaanxi Province, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China

关键词: Bach1;    Nrf2;    Heme Oxygenase-1;    Reactive oxygen species;    Homocysteine;   

Others  :  1130855
DOI  :  10.1186/1743-7075-11-55

 received in 2014-07-22, accepted in 2014-11-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Luo et al.; licensee BioMed Central Ltd.

【 图 表 】

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