Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis.
Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B(6), B(12), or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and alpha1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis.
García-Tevijano
E R
ER
División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
Berasain
C
C
Rodríguez
J A
JA
Corrales
F J
FJ
Arias
R
R
Martín-Duce
A
A
Caballería
J
J
Mato
J M
JM
Avila
M A
MA
D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D008956:Models, Chemical; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D006710:Homocysteine; D008715:Methionine