Latour Alizée, Salameh Sacha, Carbonne Christel, Daubigney Fabrice, Paul Jean-Louis, Kergoat Micheline, Autier Valérie, Delabar Jean-Maurice, De Geest Bart, Janel Nathalie
Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France.
Metabrain Research, Chilly Mazarin, France.
Mol Genet Metab Rep. 2015 Jan 13;2:51-60. doi: 10.1016/j.ymgmr.2014.12.007. eCollection 2015 Mar.
Hyperhomocysteinemia results from hepatic metabolism dysfunction and is characterized by a high plasma homocysteine level, which is also an independent risk factor for cardiovascular disease. Elevated levels of homocysteine in plasma lead to hepatic lesions and abnormal lipid metabolism. Therefore, lowering homocysteine levels might offer therapeutic benefits. Recently, we were able to lower plasma homocysteine levels in mice with moderate hyperhomocysteinemia using an adenoviral construct designed to restrict the expression of DYRK1A, a serine/threonine kinase involved in methionine metabolism (and therefore homocysteine production), to hepatocytes. Here, we aimed to extend our previous findings by analyzing the effect of hepatocyte-specific gene transfer on intermediate hyperhomocysteinemia and its associated hepatic toxicity and liver dysfunction. Commensurate with decreased plasma homocysteine and alanine aminotransferase levels, targeted hepatic expression of DYRK1A in mice with intermediate hyperhomocysteinemia resulted in elevated plasma paraoxonase-1 and lecithin:cholesterol acyltransferase activities and apolipoprotein A-I levels. It also rescued hepatic apolipoprotein E, J, and D levels. Further, Akt/GSK3/cyclin D1 signaling pathways in the liver of treated mice were altered, which may help prevent homocysteine-induced cell cycle dysfunction. gene therapy could be useful in the treatment of hyperhomocysteinemia in populations, such as end-stage renal disease patients, who are unresponsive to B-complex vitamin therapy.
高同型半胱氨酸血症源于肝脏代谢功能障碍，其特征是血浆同型半胱氨酸水平升高，这也是心血管疾病的一个独立危险因素。血浆中同型半胱氨酸水平升高会导致肝脏损伤和脂质代谢异常。因此，降低同型半胱氨酸水平可能具有治疗益处。最近，我们使用一种腺病毒构建体，将参与蛋氨酸代谢（进而参与同型半胱氨酸生成）的丝氨酸/苏氨酸激酶DYRK1A的表达限制在肝细胞中，成功降低了中度高同型半胱氨酸血症小鼠的血浆同型半胱氨酸水平。在此，我们旨在通过分析肝细胞特异性基因转移对中度高同型半胱氨酸血症及其相关肝毒性和肝功能障碍的影响来扩展我们之前的研究结果。与血浆同型半胱氨酸和丙氨酸转氨酶水平降低相一致，在中度高同型半胱氨酸血症小鼠中靶向肝脏表达DYRK1A导致血浆对氧磷酶-1和卵磷脂：胆固醇酰基转移酶活性以及载脂蛋白A-I水平升高。它还挽救了肝脏载脂蛋白E、J和D的水平。此外，经治疗小鼠肝脏中的Akt/GSK3/细胞周期蛋白D1信号通路发生了改变，这可能有助于预防同型半胱氨酸诱导的细胞周期功能障碍。基因治疗可能对诸如终末期肾病患者等对复合维生素B治疗无反应的人群的高同型半胱氨酸血症治疗有用。
