Abstract
Hyperhomocysteinemia is characterized by abnormally high concentrations of homocysteine (Hcy) in the plasma. It is a metabolic disorder associated with dysfunction of several organs such as atherosclerosis, altered lipid metabolism, and liver injury. In this study we investigated the effect of Hcy on transcriptional regulation of monocyte chemoattractant protein-1 (MCP-1), a potent chemokine, expression in hepatocytes. Hyperhomocysteinemia was induced in rats by a high-methionine diet for 4 weeks. MCP-1 mRNA and protein levels were significantly elevated in the liver tissue homogenate and in hepatocytes of hyperhomocysteinemic rats. The role of transcription factors in MCP-1 expression was examined by electrophoretic mobility shift assay. Activation of activator protein (AP)-1 but not nuclear factor kappaB was detected in the liver tissue of those rats. Incubation of rat hepatocytes with Hcy (50-200 microm) caused a significant increase in AP-1 activation followed by an increase in intracellular MCP-1 mRNA expression and an elevation of MCP-1 protein secreted into the culture medium. Hcy markedly increased the DNA binding activity of human recombinant AP-1 (c-Fos and c-Jun proteins). The presence of a sulfhydryl group in Hcy was essential for Hcy-induced AP-1 activation. When hepatocytes were transfected with decoy AP-1 oligodeoxynucleotide to inhibit AP-1 activation, Hcy-induced MCP-1 mRNA expression was abolished. Further analysis revealed that increased hepatic MCP-1 expression was positively correlated with the serum MCP-1 level. These results suggest that Hcy-induced MCP-1 expression in the liver is mediated via AP-1 activation, which may contribute to chronic inflammation associated with hyperhomocysteinemia.
Highlights
Homocysteine (Hcy)2 is a sulfhydryl group containing amino acid formed during the metabolism of methionine
It is increasingly recognized that abnormal lipid metabolism and inflammatory responses in the liver can elicit systemic inflammation, which in turn contributes to the development of cardiovascular disease (14 –16)
Increasing evidence suggests that production and secretion of proinflammatory factors in the liver plays an important role in systemic inflammation
Summary
Homocysteine (Hcy) is a sulfhydryl group containing amino acid formed during the metabolism of methionine. Nonalcoholic fatty liver disease is characterized by fat accumulation and inflammation in the liver, which is not caused by alcohol consumption (17) It is accompanied by increased serum levels of inflammatory markers and chemokines (14). Results from our previous study demonstrate that Hcy, at elevated concentrations, is able to stimulate cholesterol biosynthesis in hepatocytes leading to lipid accumulation in the liver (8). It is not known if Hcy can induce inflammatory responses such as MCP-1 expression in hepatocytes. Our results suggest that Hcy-induced MCP-1 expression in the liver is mediated via AP-1 activation
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