高同型半胱氨酸血症起因于肝脏代谢功能障碍,其特征是血浆同型半胱氨酸水平高,这也是心血管疾病的独立危险因素。血浆中同型半胱氨酸水平升高导致肝脏病变和脂质代谢异常。因此,降低同型半胱氨酸水平可能提供治疗益处.最近,我们能够使用旨在限制DYRK1A表达的腺病毒构建体来降低中度高同型半胱氨酸血症小鼠的血浆同型半胱氨酸水平,参与甲硫氨酸代谢(因此产生同型半胱氨酸)的丝氨酸/苏氨酸激酶,肝细胞。这里,我们旨在通过分析肝细胞特异性Dyrk1a基因转移对中度高同型半胱氨酸血症及其相关的肝毒性和肝功能障碍的影响来扩展我们之前的发现.与血浆同型半胱氨酸和丙氨酸转氨酶水平降低相称,在患有中度高同型半胱氨酸血症的小鼠中,DYRK1A的靶向肝表达导致血浆对氧磷酯酶-1和卵磷脂:胆固醇酰基转移酶活性和载脂蛋白A-I水平升高。它还拯救了肝脏载脂蛋白E,J,D级。Further,Akt/GSK3/cyclinD1信号通路在治疗小鼠的肝脏发生改变,这可能有助于防止同型半胱氨酸诱导的细胞周期功能障碍。DYRK1A基因疗法可用于人群高同型半胱氨酸血症的治疗,如终末期肾病患者,对复合维生素B疗法无反应的人。
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 Dyrk1a 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. DYRK1A 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.