Age-related HMG-CoA reductase deregulation depends on ROS-induced p38 activation

Valentina Pallottini, Chiara Martini, Gabriella Cavallini, Ettore Bergamini, Kirsty J. Mustard, D. Grahame Hardie, Anna Trentalance

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    Abstract

    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 and materials: In the liver of aged rats and in H2O2-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.

    Results and 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, H2O2-stimulated HepG2 cell line shows that the ROS effect on the HMG-CoAR dephosphorylation is mediated by the activation of p38/MAPK pathway. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)688-695
    Number of pages8
    JournalMechanisms of Ageing and Development
    Volume128
    Issue number11-12
    DOIs
    Publication statusPublished - 2007

    Keywords

    • ageing
    • AMPKa
    • cholesterol
    • HMG-CoAR
    • HepG2 cell line
    • liver
    • PP2A
    • p38
    • ROS
    • COENZYME-A REDUCTASE
    • PROTEIN-KINASE
    • OXIDATIVE STRESS
    • RAT-LIVER
    • CHOLESTEROL
    • HYPERCHOLESTEROLEMIA
    • PHOSPHORYLATION
    • BIOSYNTHESIS
    • CARBOXYLASE
    • MYOCYTES

    Cite this

    Pallottini, V., Martini, C., Cavallini, G., Bergamini, E., Mustard, K. J., Hardie, D. G., & Trentalance, A. (2007). Age-related HMG-CoA reductase deregulation depends on ROS-induced p38 activation. Mechanisms of Ageing and Development, 128(11-12), 688-695. https://doi.org/10.1016/j.mad.2007.10.001