3-Hydroxy-3-methylglutaryl coenzyme A reductase deregulation and age-related hypercholesterolemia: a new role for ROS.
The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is the rate-limiting enzyme in cholesterol synthesis and is highly regulated by a variety of factors. We have recently reported increased reductase activity during ageing, attributed to a higher activation state and impaired degradation of the hepatic enzyme. One of the widely recognized causes of age-related metabolic modifications is the large increase of reactive oxygen species (ROS). Therefore, the effect of ROS increase on the activity and the regulation of the HMGCoAR has been investigated in two different experimental models of ROS enriched tissue: liver from rats fed on diets deprived of either Vitamin E (Vit. E) or polyunsaturated fatty acids (Pufa). The results show that in these models, compared to that of old rats, full activation the HMGCoAR was detected while a different degradation rate is observed with the respect to old rats. Thus, our data show full correlation between ROS production and increased HMGCoAR activity. The possible therapeutic implications of these results are discussed.
Department of Biology, University of Roma Tre, Viale Marconi 446, 00146 Rome, Italy. vpallott@uniroma3.it
Valentina
V
Pallottini
Chiara
C
Martini
Andrea
A
Pascolini
Gabriella
G
Cavallini
Zina
Z
Gori
Ettore
E
Bergamini
Sandra
S
Incerpi
Anna
A
Trentalance
D000375:Aging; D000821:Animal Feed; D000818:Animals; D015153:Blotting, Western; D002790:Cholesterol 7-alpha-Hydroxylase; D004591:Electrophoresis, Polyacrylamide Gel; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000235:genetics* / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000201:enzymology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000737:chemistry; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism
D005231:Fatty Acids, Unsaturated; C432785:PPP2R1B protein, human; C086766:Ppp2r1b protein, mouse; D017382:Reactive Oxygen Species; D014810:Vitamin E; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D002790:Cholesterol 7-alpha-Hydroxylase; D010749:Phosphoprotein Phosphatases; C522189:Ppp2r1b protein, rat; D054648:Protein Phosphatase 2