Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytes

Heather L. Fox, Phuong T. Pham, Scot R. Kimball, Leonard S. Jefferson, Christopher J. Lynch

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Previous studies indicated that amino acids may activate the protein kinase activity of the target of rapamycin (TOR) and thereby augment and/or mimic the effects of insulin on protein synthesis, p70(S6k) phosphorylation, and multicellular clustering in adipocytes. To identify the individual amino acids responsible for these effects, the present study focused on the TOR substrate and translational repressor 4E-BP1. A complete mixture of amino acids stimulated the phosphorylation of 4E-BP1, decreasing its association with eukaryotic initiation factor eIF-4E. Studies on subsets of amino acids and individual amino acids showed that L-leucine was the amino acid responsible for most of the effects on 4E-BP1 phosphorylation; however, the presence of other amino acids was required to observe a maximal effect. The stimulatory effect of leucine was stereospecific and not mimicked by other branched chain amino acids but was mimicked by the leucine metabolite α- ketoisocaproate (α-KIC). The effect of α-KIC, but not leucine, was attenuated by the transaminase inhibitor (aminooxy)acetate. The latter result indicates that the effects of α-KIC required its conversion to leucine. Half-maximal stimulation of 4E-BP1 phosphorylation occurred at ~430 μM; therefore, the response was linear within the range of circulating concentrations of leucine found in various nutritional states.

Original languageEnglish (US)
Pages (from-to)C1232-C1238
JournalAmerican Journal of Physiology - Cell Physiology
Volume275
Issue number5 44-5
StatePublished - Dec 5 1998

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Adipocytes
Leucine
Phosphorylation
Amino Acids
Sirolimus
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Branched Chain Amino Acids
Metabolites
Transaminases
Protein Kinases
Cluster Analysis
Acetates
Association reactions
Insulin
Substrates
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

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title = "Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytes",
abstract = "Previous studies indicated that amino acids may activate the protein kinase activity of the target of rapamycin (TOR) and thereby augment and/or mimic the effects of insulin on protein synthesis, p70(S6k) phosphorylation, and multicellular clustering in adipocytes. To identify the individual amino acids responsible for these effects, the present study focused on the TOR substrate and translational repressor 4E-BP1. A complete mixture of amino acids stimulated the phosphorylation of 4E-BP1, decreasing its association with eukaryotic initiation factor eIF-4E. Studies on subsets of amino acids and individual amino acids showed that L-leucine was the amino acid responsible for most of the effects on 4E-BP1 phosphorylation; however, the presence of other amino acids was required to observe a maximal effect. The stimulatory effect of leucine was stereospecific and not mimicked by other branched chain amino acids but was mimicked by the leucine metabolite α- ketoisocaproate (α-KIC). The effect of α-KIC, but not leucine, was attenuated by the transaminase inhibitor (aminooxy)acetate. The latter result indicates that the effects of α-KIC required its conversion to leucine. Half-maximal stimulation of 4E-BP1 phosphorylation occurred at ~430 μM; therefore, the response was linear within the range of circulating concentrations of leucine found in various nutritional states.",
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Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytes. / Fox, Heather L.; Pham, Phuong T.; Kimball, Scot R.; Jefferson, Leonard S.; Lynch, Christopher J.

In: American Journal of Physiology - Cell Physiology, Vol. 275, No. 5 44-5, 05.12.1998, p. C1232-C1238.

Research output: Contribution to journalArticle

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AU - Fox, Heather L.

AU - Pham, Phuong T.

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AU - Jefferson, Leonard S.

AU - Lynch, Christopher J.

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