Modulation of 3-hydroxy-3-methylglutaryl-CoA reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells.

Abstract

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.

• Authors: Bruna De Felice, Mariarosaria Santillo, Rosalba Serù, Simona Damiano, Gianfranco Matrone, Robert Roy Wilson, Paolo Mondola
• Journal: Gene expression (Gene Expr) Vol. 12 Issue 1 Pg. 29-38 ( 2004) ISSN: 1052-2166 [Print] United States
• PMID: 15473258 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol
• Hydroxymethylglutaryl CoA Reductases
• Superoxide Dismutase
• Calcium

Topics

• Calcium (analysis)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Fibroblasts (metabolism)
• Gene Expression (drug effects)
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Hypercholesterolemia (drug therapy, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Superoxide Dismutase (pharmacology, therapeutic use)