Effect of Cu,Zn superoxide dismutase on cholesterol metabolism in human hepatocarcinoma (HepG2) cells

Paolo Mondola, Rosalba Serù, Mariarosaria Santillo, Simona Damiano, Maurizio Bifulco, Chiara Laezza, Pietro Formisano, Giuseppe Rotilio, Maria Rosa Ciriolo

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The microsomal enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and the low density lipoprotein (LDL) receptor pathway carry out a key role on cholesterol homeostasis in eucaryotic cells. The HMG-CoA reductase is sensitive to oxidative inactivation and to phosphorylation by many kinases that are able to inactivate the protein and increase its susceptibility to proteolysis. We previously demonstrated that a calf thymus Cu,Zn SOD affects cholesterol metabolism. This protein binds with rat hepatocyte cell membrane by a specific surface membrane receptor. The involvement of Cu,Zn SOD in cholesterol metabolism is confirmed further by the presence of this antioxidant enzyme in circulating serum lipoproteins. We studied the effect of native human Cu,Zn SOD, metal-free SOD (apo SOD), and SOD-inactivated with hydrogen peroxide on cholesterol metabolism in human hepatocarcinoma HepG2 cells. Results showed that all forms of SODs used, at the concentration of 150 ng/ml, are able to affect cholesterol metabolism decreasing both HMG-CoA reductase activity and its protein levels; this inhibitory effect is accompanied by reduced cholesterol synthesis measured as [14C]acetate incorporation into [14C]cholesterol and by an increased [125I]LDL binding to HepG2 cells. Furthermore, the inhibitory effect of Cu,Zn SOD on cholesterol synthesis was completely abolished when the cells were incubated with Cu,Zn SOD in the presence of bisindoilmaleimide (BDM), an inhibitor of protein kinase C (PKC); moreover, we demonstrated that Cu,Zn SOD as well as apo SOD was able to increase PKC activity. Overall, data demonstrate that Cu,Zn SOD affects cholesterol metabolism independently from its dismutase activity and its metal content and that the inhibitory action on cholesterol synthesis is mediated by an activation of protein kinase C.

Original languageEnglish
Pages (from-to)603-609
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume295
Issue number3
DOIs
Publication statusPublished - 2002

Fingerprint

Hep G2 Cells
Metabolism
Cholesterol
Protein Kinase C
Coenzyme A
Oxidoreductases
Metals
Superoxide Dismutase-1
Superoxide Dismutase
Proteolysis
Hydroxymethylglutaryl CoA Reductases
Thymus
Phosphorylation
Proteins
LDL Receptors
Enzymes
Cell membranes
LDL Lipoproteins
Population Groups
Thymus Gland

Keywords

  • 3-Hydroxy-3-methylglutaryl-CoA reductase
  • Cholesterol metabolism
  • Cu,Zn superoxide dismutase
  • Hepatocarcinoma (HepG2) cells
  • Protein kinase C

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Effect of Cu,Zn superoxide dismutase on cholesterol metabolism in human hepatocarcinoma (HepG2) cells. / Mondola, Paolo; Serù, Rosalba; Santillo, Mariarosaria; Damiano, Simona; Bifulco, Maurizio; Laezza, Chiara; Formisano, Pietro; Rotilio, Giuseppe; Rosa Ciriolo, Maria.

In: Biochemical and Biophysical Research Communications, Vol. 295, No. 3, 2002, p. 603-609.

Research output: Contribution to journalArticle

Mondola, Paolo ; Serù, Rosalba ; Santillo, Mariarosaria ; Damiano, Simona ; Bifulco, Maurizio ; Laezza, Chiara ; Formisano, Pietro ; Rotilio, Giuseppe ; Rosa Ciriolo, Maria. / Effect of Cu,Zn superoxide dismutase on cholesterol metabolism in human hepatocarcinoma (HepG2) cells. In: Biochemical and Biophysical Research Communications. 2002 ; Vol. 295, No. 3. pp. 603-609.
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AU - Mondola, Paolo

AU - Serù, Rosalba

AU - Santillo, Mariarosaria

AU - Damiano, Simona

AU - Bifulco, Maurizio

AU - Laezza, Chiara

AU - Formisano, Pietro

AU - Rotilio, Giuseppe

AU - Rosa Ciriolo, Maria

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