Jacobs René L, Jiang Hua, Kennelly John P, Orlicky David J, Allen Robert H, Stabler Sally P, Maclean Kenneth N
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G2E1, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2E1, Canada.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Mol Genet Metab. 2017 Apr;120(4):325-336. doi: 10.1016/j.ymgme.2017.02.010. Epub 2017 Mar 2.
Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC). Comparative metabolomic analysis of HO mouse liver revealed decreased levels of choline, and choline phosphate indicating disruption of the Kennedy pathway. Alterations in the relative levels of multiple species of PL included significant increases in PL degradation products consistent with enhanced membrane PL turnover. A significant decrease in PC containing 20:4n6 which primarily formed by the methylation of phosphatidylethanolamine to PC was consistent with decreased flux through PEMT. Hepatic expression of PEMT in both the cbs-/- and HO models is post-translationally repressed with decreased levels of PEMT protein and activity that inversely-correlates with the scale of liver injury. Failure to induce further repression of PEMT in HO mice by increased homocysteine, methionine and S-adenosylhomocysteine or depletion of glutathione combined with examination of multiple homocysteine-independent models of liver injury indicated that repression of PEMT in HCU is a consequence rather than a cause of liver injury. Collectively, our data show significant alteration of a broad range of hepatic PL and choline metabolism in HCU with the potential to contribute to multiple aspects of pathogenesis in this disease.
由于胱硫醚β-合酶（CBS）失活突变导致的经典型同型胱氨酸尿症（HCU）是一种人们了解较少的危及生命的先天性硫代谢紊乱疾病。先前描述的cbs-/-小鼠模型由于新生儿肝衰竭而表现出半致死表型。HCU的转基因HO小鼠模型仅表现出轻度肝损伤，并概括了该疾病在人类中发生时的多个方面。HCU中蛋氨酸循环的破坏有可能通过破坏肯尼迪途径和磷脂酰乙醇胺N-甲基转移酶（PEMT）介导的磷脂酰胆碱（PC）合成来影响磷脂（PL）代谢的多个方面。对HO小鼠肝脏的比较代谢组学分析显示胆碱和磷酸胆碱水平降低，表明肯尼迪途径受到破坏。多种PL相对水平的改变包括PL降解产物显著增加，这与增强的膜PL周转一致。主要由磷脂酰乙醇胺甲基化形成PC的含20:4n6的PC显著减少，这与通过PEMT的通量降低一致。在cbs-/-和HO模型中，肝脏中PEMT的表达在翻译后受到抑制，PEMT蛋白和活性水平降低，这与肝损伤程度呈负相关。通过增加同型半胱氨酸、蛋氨酸和S-腺苷同型半胱氨酸或消耗谷胱甘肽未能进一步诱导HO小鼠中PEMT的抑制，结合对多种同型半胱氨酸非依赖性肝损伤模型的检查表明，HCU中PEMT的抑制是肝损伤的结果而非原因。总体而言，我们的数据表明HCU中广泛的肝脏PL和胆碱代谢发生了显著改变，有可能导致该疾病发病机制的多个方面。
