Age-related HMG-CoA reductase deregulation depends on ROS-induced p38 activation.
BACKGROUND
It seems to be clear that hepatic age-related HMG-CoA reductase total activation is connected to a rise of reactive oxygen species (ROS). However, the mechanism by which ROS achieve this effect is unknown. Thus, in this work, we have performed a study of HMG-CoAR by analyzing the enzymes involved in its short-term regulation, namely, AMP-activated kinase (AMPK) and protein phosphatase 2A (PP2A).


METHODS
In the liver of aged rats and in H(2)O(2)-stimulated HepG2 cells the ROS content, the HMG-CoA reductase activation state, its regulatory enzymes and the p38 downstream pathway involved in reductase deregulation, have been studied.


CONCLUSIONS
Our data show that the hepatic HMG-CoAR is completely dephosphorylated in the liver of old rat being the PP2A increased association with HMG-CoAR the main responsible. On the other hand, the age-related greater association between PP2A and HMG-CoAR results to be due to an increase in ROS that is present during aging and has already been demonstrated to influence HMG-CoAR activation state. Moreover, H(2)O(2)-stimulated HepG2 cell line shows that the ROS effect on the HMG-CoAR dephosphorylation is mediated by the activation of p38/MAPK pathway.
Pallottini
Valentina
V
Department of Biology, University of Rome "Roma Tre", Viale Marconi 446, 00146 Rome, Italy. vpallott@uniroma3.it
Martini
Chiara
C
Cavallini
Gabriella
G
Bergamini
Ettore
E
Mustard
Kirsty J
KJ
Hardie
D Grahame
DG
Trentalance
Anna
A
D055372:AMP-Activated Protein Kinases; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D006903:Hydroxymethylglutaryl CoA Reductases; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2