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.