Modulation of 3-hydroxy-3-methylglutaryl-CoA reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells.
The homeostasis of intracellular cholesterol in animal cells is highly regulated by a complex system in which the microsomal rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase plays a key role in cholesterol synthesis. Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase (SOD1) inhibits the HMG-CoA reductase activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis. Although these data suggest that SOD1 exerts a physiological role in cholesterol metabolism, it is still unclear whether the decrease of HMG-CoA reductase activity is mediated by transcriptional or by posttranscriptional events. The results of the present study, obtained by one-step RT-PCR assay, demonstrated that both SOD1 and the metal-free form of enzyme (Apo SOD1) inhibit HMG-CoA reductase gene expression in hepatocarcinoma HepG2 cells, in normal human fibroblasts, and in fibroblasts of subjects affected by familiar hypercholesterolemia. Accordingly, SOD1 could be used as a potential agent in the treatment of hypercholesterolemia, even in subjects lacking a functional LDL receptor pathway.
De Felice
Bruna
B
Department of Life Sciences, University of Naples 2, Via Vivaldi, 43, Caserta, Italy.
Santillo
Mariarosaria
M
Serù
Rosalba
R
Damiano
Simona
S
Matrone
Gianfranco
G
Wilson
Robert Roy
RR
Mondola
Paolo
P
D002118:Calcium / Q000032:analysis; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000494:pharmacology* / Q000627:therapeutic use
D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013482:Superoxide Dismutase; D002118:Calcium