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Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis

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Abstract

The liver is the major contributor to homocysteine (Hcy) metabolism and fatty liver disease is associated with hyperhomocysteinemia. Bleomycin hydrolase (Blmh) is an aminohydrolase that also participates in Hcy metabolism by hydrolyzing Hcy-thiolactone. To gain insight into hepatic functions of Blmh, we analyzed the liver proteome of Blmh −/− and Blmh +/+ mice in the absence and presence of diet-induced (high methionine) hyperhomocysteinemia using 2D IEF/SDS-PAGE gel electrophoresis and MALDI–TOF mass spectrometry. We identified eleven liver proteins whose expression was significantly altered as a result of the Blmh gene inactivation. The differential expression (Blmh −/− vs. Blmh +/+) of four liver proteins was lower, of two proteins was higher, and was further modified in mice fed with a hyperhomocysteinemic high-Met diet. The down-regulated proteins are involved in lipoprotein metabolism (ApoA1, ApoE), antigen processing (Psme1), energy metabolism (Atp5h, Gamt), methylglyoxal detoxification (Glo1), oxidative stress response (Sod1), and inactivation of catecholamine neurotransmitters (Comt). The two up-regulated proteins are involved in nitric oxide generation (Ddah1) and xenobiotic detoxification (Sult1c1). We also found that livers of Blmh −/− mice expressed a novel variant of glyoxalase domain-containing protein 4 (Glod4) by a post-transcriptional mechanism. Our findings suggest that Blmh interacts with diverse cellular processes—from lipoprotein metabolism, nitric oxide regulation, antigen processing, and energy metabolism to detoxification and antioxidant defenses—that are essential for liver homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in fatty liver disease.

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Abbreviations

Hcy:

Homocysteine

Blmh:

Bleomycin hydrolase

Cbs:

Cystathionine β-synthase

ApoA1:

Apolipoprotein A1

ApoE:

Apolipoprotein E

Psme1:

Proteasome activator complex subunit 1

Atp5 h:

ATPase subunit d

Gamt:

Guanidinoacetate-N-methyltransferase

Glo1:

Methylglyoxylase 1

Sod1:

Superoxide dismutase

Comt:

Catechol-O-methyltransferase

Ddah1:

Dimethylarginine dimethylaminohydrolase 1

Sult1c1:

Phenolsulphotransferase

IEF/SDS-PAGE:

Isoelectric focusing/sodium dodecylsulphate polyacrylamide gel electrophoresis

MALDI–TOF:

Matrix-assisted laser desorption ionization–time of flight

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Acknowledgments

We thank John Lazo for kindly providing a breeding pair of Blmh-null mice. This work was supported in part by grants from the American Heart Association, the National Science Center, Poland (2011/01/B/NZ1/03417, 2011/02/A/NZ1/00010, 2012/07/B/NZ7/01178, and 2013/09/B/NZ5/02794) and MNiSW, Poland (N401 065321504, N N302 434439).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Bioorganic Chemistry, Poznań, Poland

    Joanna Suszyńska-Zajczyk, Jacek Wróblewski, Olga Utyro, Magdalena Łuczak, Łukasz Marczak & Hieronim Jakubowski

  2. Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland

    Hieronim Jakubowski

  3. Department of Microbiology and Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, 225 Warren Street, Newark, NJ, 07101-1709, USA

    Joanna Suszyńska-Zajczyk & Hieronim Jakubowski

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  1. Joanna Suszyńska-Zajczyk
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  2. Jacek Wróblewski
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Correspondence to Hieronim Jakubowski.

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J. Suszyńska-Zajczyk and J. Wróblewski contributed equally to this work.

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Supplementary material contains supplemental Experimental Procedures, Fig. S1, and Table S1.

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Suszyńska-Zajczyk, J., Wróblewski, J., Utyro, O. et al. Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis. Amino Acids 46, 1471–1480 (2014). https://doi.org/10.1007/s00726-014-1712-4

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