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J. Biol. Chem., Vol. 277, Issue 45, 43281-43287, November 8, 2002
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From the Central Arkansas Veterans HealthCare System, and
Department of Medicine, Division of Endocrinology, and the
Department of Geriatrics, University of Arkansas for Medical Sciences,
Little Rock, Arkansas 72205
The balance of lipid flux in adipocytes is
controlled by the opposing actions of lipolysis and lipogenesis, which
are controlled primarily by hormone-sensitive lipase and
lipoprotein lipase (LPL), respectively. Catecholamines stimulate
adipocyte lipolysis through reversible phosphorylation of
hormone-sensitive lipase, and simultaneously inhibit LPL activity.
However, LPL regulation is complex and previous studies have described
translational regulation of LPL in response to catecholamines because
of an RNA-binding protein that interacts with the 3'-untranslated
region of LPL mRNA. In this study, we identified several protein
components of an LPL RNA binding complex. Using an LPL RNA affinity
column, we identified two of the RNA-binding proteins as the catalytic
(C) subunit of cAMP-dependent protein kinase (PKA), and A
kinase anchoring protein (AKAP) 121/149, one of the PKA anchoring
proteins, which has known RNA binding activity. To determine whether
the C subunit was involved in LPL translation inhibition, the C subunit
was depleted from the cytoplasmic extract of epinephrine-stimulated
adipocytes by immunoprecipitation. This resulted in the loss of LPL
translation inhibition activity of the extract, along with decreased
RNA binding activity in a gel shift assay. To demonstrate the
importance of the AKAPs, inhibition of PKA-AKAP binding with a peptide
competitor (HT31) prevented epinephrine-mediated inhibition of LPL
translation. C subunit kinase activity was necessary for LPL RNA
binding and translation inhibition, suggesting that the phosphorylation
of AKAP121/149 or other proteins was an important part of RNA binding
complex formation. The hormonal activation of PKA results in the
reversible phosphorylation of hormone-sensitive lipase, which is the
primary mediator of adipocyte lipolysis. These studies demonstrate a
dual role for PKA to simultaneously inhibit LPL-mediated
lipogenesis through inhibition of LPL translation.
The Translational Regulation of Lipoprotein Lipase
by Epinephrine Involves an RNA Binding Complex Including the Catalytic
Subunit of Protein Kinase A*
*
This work was supported by a Career Development Award from
the American Diabetes Association (to G. R.), Grant DK 39176 from the National Institute of Health, and a Merit Review Grant from the
Veterans Administration.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Research, 151 LR,
Central Arkansas Veterans Healthcare System, 4300 W. 7th St., Little
Rock, AR 72205. Tel.: 501-257-4816; Fax: 501-257-4821; E-mail:
kernphilipa@uams.edu.
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