Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis
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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.
KeywordsBleomycin hydrolase High methionine diet Hyperhomocysteinemia Mouse liver proteome
Proteasome activator complex subunit 1
- Atp5 h
ATPase subunit d
Dimethylarginine dimethylaminohydrolase 1
Isoelectric focusing/sodium dodecylsulphate polyacrylamide gel electrophoresis
Matrix-assisted laser desorption ionization–time of flight
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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