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.