Hamelet Julien, Noll Christophe, Ripoll Clémentine, Paul Jean-Louis, Janel Nathalie, Delabar Jean-Maurice
EA 3508 - case 7104, Univ Paris Diderot, 75205 Paris cedex 13, France.
Biochem Biophys Res Commun. 2009 Jan 16;378(3):673-7. doi: 10.1016/j.bbrc.2008.11.126. Epub 2008 Dec 6.
Hyperhomocysteinemia due to cystathionine beta synthase (CBS)-deficiency confers diverse clinical manifestations, notably liver diseases. Even if hyperhomocysteinemia in liver of CBS-deficient mice, a murine model of hyperhomocysteinemia, promotes mitochondrial oxidative stress and pro-apoptotic signals, protective signals may counteract these pro-apoptotic signals, leading to chronic inflammation. As DYRK1A, a serine/threonine kinase, has been described as a candidate antiapoptotic factor, we have analyzed the expression of DYRK1A in liver of CBS-deficient mice. We found that DYRK1A protein level was reduced in liver of CBS-deficient mice, which was not observed at the gene expression level. Moreover, the use of primary hepatocytes/Kupffer cells co-culture showed that degradation of DYRK1A induced by hyperhomocysteinemia requires calpain activation. Our results demonstrate a deleterious effect of hyperhomocysteinemia on DYRK1A protein expression, and emphasize the role of hyperhomocysteinemia on calpain activation.
由于胱硫醚β合酶（CBS）缺乏导致的高同型半胱氨酸血症具有多种临床表现，尤其是肝脏疾病。即使在CBS缺乏小鼠（一种高同型半胱氨酸血症的小鼠模型）的肝脏中，高同型半胱氨酸血症会促进线粒体氧化应激和促凋亡信号，但保护信号可能会抵消这些促凋亡信号，从而导致慢性炎症。由于丝氨酸/苏氨酸激酶DYRK1A已被描述为一种候选抗凋亡因子，我们分析了DYRK1A在CBS缺乏小鼠肝脏中的表达。我们发现，CBS缺乏小鼠肝脏中DYRK1A蛋白水平降低，而在基因表达水平上未观察到这种情况。此外，原代肝细胞/库普弗细胞共培养实验表明，高同型半胱氨酸血症诱导的DYRK1A降解需要钙蛋白酶激活。我们的结果证明了高同型半胱氨酸血症对DYRK1A蛋白表达具有有害影响，并强调了高同型半胱氨酸血症在钙蛋白酶激活中的作用。
