Inhibition of Extracellular Signal–Regulated Kinase in Liver of Hyperhomocysteinemic Mice

Abstract

To the Editor: We read with great interest the article by Woo et al,1 reporting the involvement of cAMP-dependent protein kinase A (cAMP-PKA) signaling pathway in activation of the transcription factor cAMP-response element binding protein (CREB) during hyperhomocysteinemia in the liver. Hyperhomocysteinemia, defined as elevated homocysteine (Hcy) levels in blood, is not only associated with cardiovascular and cerebrovascular disorders, but is also accompanied by hepatic steatosis.2 As CREB plays an important role in the expression of genes involved in lipid metabolism, the work of Woo et al1 is of great importance to show the mechanism by which Hcy induces CREB activation. Among the signaling pathways important for activation of CREB, protein kinases such as PKA, extracellular signal regulated-kinase (ERK), and p38 mitogen-activating protein (p38 MAP) kinase are able to phosphorylate CREB leading to its activation.3 Woo et al1 demonstrated, by incubation of hepatocytes with inhibitor of protein kinases, that Hcy-induced CREB activation is mediated by PKA signaling pathway, but not by ERK pathway or p38 MAP kinase pathway. These results are very intriguing because we have showed the involvement of ERK and PKA signaling pathways in the Hcy-induced CREB activation in …