Jakubowski Hieronim, Perla-Kaján Joanna, Finnell Richard H, Cabrera Robert M, Wang Hong, Gupta Sapna, Kruger Warren D, Kraus Jan P, Shih Diana M
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA.
FASEB J. 2009 Jun;23(6):1721-7. doi: 10.1096/fj.08-127548. Epub 2009 Feb 9.
Genetic disorders of homocysteine (Hcy) or folate metabolism or high-methionine diets elevate plasma Hcy and its atherogenic metabolite Hcy-thiolactone. In humans, severe hyperhomocysteinemia due to genetic alterations in cystathionine beta-synthase (Cbs) or methylenetetrahydrofolate reductase (Mthfr) results in neurological abnormalities and premature death from vascular complications. In mouse models, dietary or genetic hyperhomocysteinemia results in liver or brain pathological changes and accelerates atherosclerosis. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates modified proteins (N-Hcy-protein) with autoimmunogenic and prothrombotic properties. Our aim was to determine how N-Hcy-protein levels are affected by genetic or nutritional disorders in Hcy or folate metabolism in mice. We found that plasma N-Hcy-protein was elevated 10-fold in mice fed a high-methionine diet compared with the animals fed a normal commercial diet. We also found that inactivation of Cbs, Mthfr, or the proton-coupled folate transporter (Pcft) gene resulted in a 10- to 30-fold increase in plasma or serum N-Hcy-protein levels. Liver N-Hcy-protein was elevated 3.4-fold in severely and 11-fold in extremely hyperhomocysteinemic Cbs-deficient mice, 3.6-fold in severely hyperhomocysteinemic Pcft mice, but was not elevated in mildly hyperhomocysteinemic Mthfr-deficient animals, suggesting that mice have a capacity to prevent accumulation of N-Hcy-protein in their organs. These findings provide evidence that N-Hcy-protein is an important metabolite associated with Hcy pathophysiology in the mouse.
同型半胱氨酸（Hcy）或叶酸代谢的遗传紊乱，或高蛋氨酸饮食会使血浆Hcy及其致动脉粥样硬化代谢物Hcy-硫内酯升高。在人类中，由于胱硫醚β-合酶（Cbs）或亚甲基四氢叶酸还原酶（Mthfr）的基因改变导致的严重高同型半胱氨酸血症会导致神经异常，并因血管并发症而过早死亡。在小鼠模型中，饮食性或遗传性高同型半胱氨酸血症会导致肝脏或大脑发生病理变化，并加速动脉粥样硬化。Hcy-硫内酯能够与蛋白质赖氨酸残基形成异肽键，从而产生具有自身免疫原性和促血栓形成特性的修饰蛋白（N-Hcy-蛋白）。我们的目的是确定小鼠Hcy或叶酸代谢中的遗传或营养紊乱如何影响N-Hcy-蛋白水平。我们发现，与喂食正常商业饮食的动物相比，喂食高蛋氨酸饮食的小鼠血浆N-Hcy-蛋白升高了10倍。我们还发现，Cbs、Mthfr或质子偶联叶酸转运体（Pcft）基因的失活导致血浆或血清N-Hcy-蛋白水平升高10至30倍。在严重高同型半胱氨酸血症的Cbs缺陷小鼠中，肝脏N-Hcy-蛋白升高了3.4倍，在极度高同型半胱氨酸血症的小鼠中升高了11倍；在严重高同型半胱氨酸血症的Pcft小鼠中升高了3.6倍，但在轻度高同型半胱氨酸血症的Mthfr缺陷动物中未升高，这表明小鼠有能力防止N-Hcy-蛋白在其器官中积累。这些发现提供了证据，表明N-Hcy-蛋白是与小鼠Hcy病理生理学相关的一种重要代谢物。
