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Effect of simvastatin, an inhibitor of hydroxy‐methylglutaryl coenzyme a reductase, on the growth of human ito cells
Author(s) -
Mallat Ariane,
Preaux AnneMarie,
Blazejewski Sylvie,
Dhumeaux Daniel,
Rosenbaum Jean,
Mavier Philippe
Publication year - 1994
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840200631
Subject(s) - simvastatin , reductase , mevalonic acid , geranylgeraniol , biochemistry , geranylgeranyl pyrophosphate , hydroxymethylglutaryl coa reductase , hmg coa reductase , coenzyme a , biology , lovastatin , farnesyl pyrophosphate , endocrinology , medicine , chemistry , cholesterol , farnesol , enzyme , biosynthesis
During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy‐methylglutaryl–coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle α‐actin. Simvastatin (0.1 to 10 μmol/L) induced a marked dose‐dependent decrease of [ 3 H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin‐induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy‐methylglutaryl–coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [ 3 H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol‐low‐density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N‐linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study. (Hepatology 1994;20:1589–1594).

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