Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside

Ali K. Reiter, Douglas R. Bolster, Stephen Crozier, Scot Kimball, Leonard "Jim" Jefferson

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Abstract

The studies described herein were designed to investigate the effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR), an activator of the AMP-activated protein kinase (AMPK), on the transnational control of protein synthesis and signaling through the mammalian target of rapamycin (mTOR) in rat liver. Effects of AICAR observed in vivo were compared with those obtained in an in situ perfused liver preparation to investigate activation of AMPK in the absence of accompanying changes in hormones and nutrients. AMPK became hyperphosphorylated, as assessed by a gel-shift analysis, in response to AICAR both in vivo and in situ; however, increased relative phosphorylation at the Thr172 site on the kinase was observed only in perfused liver. Phosphorylation of AMPK either in vivo or in situ was associated with a repression of protein synthesis as well as decreased phosphorylation of a number of targets of mTOR signaling including ribosomal protein S6 kinase 1, eukaryotic initiation factor (eIF)4G, and eIF4E-binding protein (4E-BP)1. The phosphorylation changes in eIF4G and 4E-BP1 were accompanied by a reduction in the amount of eIF4E present in the active eIF4E·eIF4G complex and an increase in the amount present in the inactive eIF4E·4E-BP1 complex. Reduced insulin signaling as well as differences in nutrient availability may have contributed to the effects observed in vivo as AICAR caused a fall in the serum insulin concentration. Overall, however, the results from both experimental models support a scenario in which AICAR directly represses protein synthesis and mTOR signaling in the liver through an AMPK-dependent mechanism.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume288
Issue number5 51-5
DOIs
StatePublished - May 1 2005

Fingerprint

Aminoimidazole Carboxamide
Ribonucleosides
AMP-Activated Protein Kinases
Sirolimus
Phosphorylation
Liver
Rats
Proteins
Nutrients
Eukaryotic Initiation Factor-4G
Insulin
Ribosomal Protein S6 Kinases
Food
Electrophoretic Mobility Shift Assay
Carrier Proteins
Theoretical Models
Phosphotransferases
Gels
Chemical activation
acadesine

All Science Journal Classification (ASJC) codes

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

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title = "Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside",
abstract = "The studies described herein were designed to investigate the effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR), an activator of the AMP-activated protein kinase (AMPK), on the transnational control of protein synthesis and signaling through the mammalian target of rapamycin (mTOR) in rat liver. Effects of AICAR observed in vivo were compared with those obtained in an in situ perfused liver preparation to investigate activation of AMPK in the absence of accompanying changes in hormones and nutrients. AMPK became hyperphosphorylated, as assessed by a gel-shift analysis, in response to AICAR both in vivo and in situ; however, increased relative phosphorylation at the Thr172 site on the kinase was observed only in perfused liver. Phosphorylation of AMPK either in vivo or in situ was associated with a repression of protein synthesis as well as decreased phosphorylation of a number of targets of mTOR signaling including ribosomal protein S6 kinase 1, eukaryotic initiation factor (eIF)4G, and eIF4E-binding protein (4E-BP)1. The phosphorylation changes in eIF4G and 4E-BP1 were accompanied by a reduction in the amount of eIF4E present in the active eIF4E·eIF4G complex and an increase in the amount present in the inactive eIF4E·4E-BP1 complex. Reduced insulin signaling as well as differences in nutrient availability may have contributed to the effects observed in vivo as AICAR caused a fall in the serum insulin concentration. Overall, however, the results from both experimental models support a scenario in which AICAR directly represses protein synthesis and mTOR signaling in the liver through an AMPK-dependent mechanism.",
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Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside. / Reiter, Ali K.; Bolster, Douglas R.; Crozier, Stephen; Kimball, Scot; Jefferson, Leonard "Jim".

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 288, No. 5 51-5, 01.05.2005.

Research output: Contribution to journalArticle

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AU - Reiter, Ali K.

AU - Bolster, Douglas R.

AU - Crozier, Stephen

AU - Kimball, Scot

AU - Jefferson, Leonard "Jim"

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AB - The studies described herein were designed to investigate the effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR), an activator of the AMP-activated protein kinase (AMPK), on the transnational control of protein synthesis and signaling through the mammalian target of rapamycin (mTOR) in rat liver. Effects of AICAR observed in vivo were compared with those obtained in an in situ perfused liver preparation to investigate activation of AMPK in the absence of accompanying changes in hormones and nutrients. AMPK became hyperphosphorylated, as assessed by a gel-shift analysis, in response to AICAR both in vivo and in situ; however, increased relative phosphorylation at the Thr172 site on the kinase was observed only in perfused liver. Phosphorylation of AMPK either in vivo or in situ was associated with a repression of protein synthesis as well as decreased phosphorylation of a number of targets of mTOR signaling including ribosomal protein S6 kinase 1, eukaryotic initiation factor (eIF)4G, and eIF4E-binding protein (4E-BP)1. The phosphorylation changes in eIF4G and 4E-BP1 were accompanied by a reduction in the amount of eIF4E present in the active eIF4E·eIF4G complex and an increase in the amount present in the inactive eIF4E·4E-BP1 complex. Reduced insulin signaling as well as differences in nutrient availability may have contributed to the effects observed in vivo as AICAR caused a fall in the serum insulin concentration. Overall, however, the results from both experimental models support a scenario in which AICAR directly represses protein synthesis and mTOR signaling in the liver through an AMPK-dependent mechanism.

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