title: Short- and long-term regulation of 3-hydroxy 3-methylglutaryl coenzyme A reductase by a 4-methylcoumarin.
abstract: Dyslipidemia is one of the most significant risk factors for cardiovascular diseases. Cholesterol homeostasis is regulated by both the receptor-mediated endocytosis of Low Density Lipoproteins by LDL receptors and de novo cholesterol synthesis via the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. Although statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase substrate competitors, have revolutionized the management of cardiovascular diseases by lowering serum LDL, their side effects range from myalgia to rhabdomyolysis. Treatment with antioxidant compounds could represent an efficient alternative in the modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Indeed it has already been demonstrated that the rise in reactive oxygen species levels causes the complete dephosphorylation and, in turn activation of the enzyme. Many coumarins and their derivatives have the special ability to scavenge reactive oxygen species or show a lipid lowering potential. Here we evaluated whether the coumarin, 4-methylesculetin could exert both the ability to scavenge ROS and to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase in HepG2 cell line where the enzyme activity dysregulation induced by reactive oxygen species has already been reported. The antioxidant property of 4-methylesculetin led to the reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activation state through the increase of the enzyme phosphorylation. In addition, this coumarin showed the ability to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase protein levels both by transcriptional and degradational events independent of its antioxidant activity.
authors.affiliation: Department of Biology, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Trapani
authors.forename: Marco
authors.initials: M
authors.lastname: Segatto
authors.forename: Veronica
authors.initials: V
authors.lastname: Simeoni
authors.forename: Valentina
authors.initials: V
authors.lastname: Balducci
authors.forename: Ashish
authors.initials: A
authors.lastname: Dhawan
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.forename: Sandra
authors.initials: S
authors.lastname: Incerpi
authors.forename: Valentina
authors.initials: V
authors.lastname: Pallottini
mesh_terms: D015153:Blotting, Western; D020134:Catalytic Domain; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D015394:Molecular Structure; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013997:Time Factors; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003374:Coumarins; D016877:Oxidants; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014468:Umbelliferones; C096882:6,7-dihydroxy-4-methylcoumarin; D006861:Hydrogen Peroxide; D006903:Hydroxymethylglutaryl CoA Reductases; D054648:Protein Phosphatase 2