Hyperhomocysteinemia in liver cirrhosis mechanisms and role in vascular and hepatic fibrosis

Numerous clinical and epidemiological studies have identified elevated homo cysteine levels in plasma as a risk factor for atherosclerotic vascular dis ease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions lead ing to vitamin B-6, B-12, or folate deficiencies; or chronic alcohol consum ption. Homocysteine is an intermediate in methionine metabolism, which take s place mainly in the liver. Impaired liver function leads to altered methi onine and homocysteine metabolism; however, the molecular basis for such al terations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the presen t work, we have examined the expression of the main enzymes involved in met hionine and homocysteine metabolism, along with the plasma levels of methio nine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homoc ysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have obs erved a marked reduction in the expression of the main genes involved in ho mocysteine metabolism in liver cirrhosis. In addition, we have identified t he tissue inhibitor of metalloprotemases-1 and alpha1(I)procollagen to be u pregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observ ations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocys teine levels in the development of liver Fibrosis.