Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver.
As the main risk factor for cardiovascular disease, hypercholesterolemia is one of the most studied age-related metabolic alterations. In the liver, cholesterol homeostasis is strictly regulated through the modulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. With ageing, hepatic HMG-CoA reductase becomes completely activated and cholesterol content increases in the blood. The research reported in this paper uses the regulatory enzymes of reductase (i.e., the AMP-dependent kinase (AMPK) and the protein phosphatase 2A (PP2A)), the HMG-CoA reductase thermodependent activity and the "in vitro" enzyme degradation to elucidate the role played by the HMG-CoA reductase regulation and its membrane interaction. Related experiments were performed on 3 and 24 months "ad libitum" (AL) fed rats and 24 months caloric-restricted rats. The results show no changes in the PP2A level and the activation state of AMP dependent kinase in aged "ad libitum" fed rats. By contrast, the activation state of the kinase is enhanced in the aged caloric-restricted animals. With respect to the adult, the thermodependent activity of reductase remains unchanged, while the degradation rate of the HMG-CoA reductase is slower and independent on proteasome. These findings support the hypothesis that a different arrangement of the HMG-CoA reductase membrane domain in aged rats is a cause of reductase deregulation.
Pallottini
Valentina
V
Department of Biology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy.
Montanari
Laura
L
Cavallini
Gabriella
G
Bergamini
Ettore
E
Gori
Zina
Z
Trentalance
Anna
A
D055372:AMP-Activated Protein Kinases; D000375:Aging / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D004789:Enzyme Activation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D009097:Multienzyme Complexes; D006903:Hydroxymethylglutaryl CoA Reductases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex