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

Gene Expr. 2004;12(1):29-38. doi: 10.3727/000000004783992198.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Superoxide Dismutase
  • Calcium