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ORIGINAL RESEARCH ARTICLE

Moderately High Folic Acid Supplementation Exacerbates Experimentally Induced Liver Fibrosis in Rats

Judit Marsillach^*, Natàlia Ferré, Jordi Camps^*,1, Francesc Riu^*, Anna Rull^* and Jorge Joven^*

^* Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut de Recerca en Ciències de la Salut, Reus, Spain; Department of Clinical Biochemistry and Molecular Genetics, Hospital Clínic Universitari, Barcelona, Spain

To whom requests for reprints should be addressed at ¹ Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, C. Sant Joan s/n, 43201 Reus, Catalunya, Spain. E-mail: jcamps{at}grupsagessa.cat

Under certain clinical circumstances, folic acid can have undesirable effects. We investigated the following: (i) the effects of moderately high folic acid supplementation on the course of liver impairment in CCl₄-treated rats and (ii) the influence of folic acid supplements on the hepatic recovery following the interruption of the CCl₄-induced toxic injury. Four experimental groups of rats were used: CCl₄-treated rats (0.5 ml of CCl₄ twice a week ip) fed standard chow for up to 12 weeks (Group A); treated rats fed chow supplemented with 25 mg/kg folic acid from weeks 6 to 12 (Group B); treated rats fed a standard diet but with CCl₄ discontinued after 6 weeks to allow for tissue recovery over 4 weeks (Group C); rats as Group C but fed a diet supplemented with 25 mg/kg folic acid from weeks 6 to 10 (Group D). Liver and blood samples were obtained for biochemical, histological, and gene expression analyses. Animals that received the supplement had a higher content of collagen, activated stellate cells, and apoptotic parenchymal cells in biopsy tissue at weeks 8 and 10 of treatment and more extensive alterations in serum albumin and bilirubin concentrations (Group B vs. Group A). In some of the time periods analyzed, alterations were observed in the expression of genes related to apoptosis (B-cell leukemia/lymphoma 2, inhibitor of apoptosis 2) and to fibrosis (procollagen I, matrix metalloproteinase 7). In the recovery period (Groups C and D), folic acid administration was associated with increased hepatic inflammation and apoptosis and with a decrease in the tissue inhibitor of metalloproteinase-3 expression following 1 week of recovery. We conclude that folic acid administration aggravates the development of fibrosis in CCl₄-treated rats. Follow-up studies are needed to determine whether folic acid treatment would be contraindicated in patients with chronic liver diseases.

Key Words: apoptosis • fibrosis • folic acid • gene expression • nutrition