title: IGF-I induced phosphorylation of S6K1 and 4E-BP1 in heart is impaired by acute alcohol intoxication.
abstract: BACKGROUND
  The purpose of the present study was to determine whether acute alcohol (EtOH) intoxication impairs the signal transduction pathway used to coordinate insulin-like growth factor (IGF)-I stimulation of myocardial protein synthesis.
  
  
  METHODS
  Rats were injected intraperitoneally with EtOH or saline. After 2.5 h, IGF-I or saline was injected intravenously and the heart was excised at 2 min or 20 min. Additional rats were pretreated with RU486 or tumor necrosis factor (TNF) binding protein (BP) to assess the importance of elevations in glucocorticoids or TNF, respectively, as endogenous modulators of IGF-I signal transduction.
  
  
  RESULTS
  EtOH did not alter the total amount or tyrosine phosphorylation of the IGF-I receptor, IRS-1 or PKB under basal or IGF-stimulated conditions. However, EtOH attenuated the ability of IGF-I to phosphorylate ribosomal S6 kinase (S6K)-1 on residues T389 ( approximately 62%) and T421/S424 ( approximately 40%), and also reduced ribosomal protein S6 phosphorylation. Under basal conditions, EtOH altered the distribution of eukaryotic initiation factor (eIF) 4E, as evidenced by a decreased amount of the active eIF4E.eIF4G complex (53%), an increased amount of inactive eIF4E.4E-BP1 complex ( approximately 3-fold), and decreased phosphorylation of 4E-BP1 (56%). EtOH also impaired the ability of IGF-I to reverse the above-mentioned changes in the eIF4E system. Pretreatment of rats with RU486 or TNFBP was unable to attenuate the EtOH-induced changes in either eIF4E distribution or the phosphorylation state of 4E-BP1, S6K1 or S6.
  
  
  CONCLUSIONS
  These data indicate that acute EtOH intoxication alters selected aspects of translational control in the heart under basal conditions. Furthermore, despite appropriate stimulation of IGF-I receptor, IRS-1 and PKB, EtOH impairs IGF-I signaling via S6K1 and 4E-BP1 pathways, and this defect is regulated in a glucocorticoid- and TNF-independent manner. This IGF-I resistance may represent a participating mechanism by which alcohol limits protein synthesis in heart.
authors.affiliation: Prevention Research Center, 2150 Shattuck Avenue, Suite 900, Berkeley, CA 94704, USA. bfreisthler@prev.org
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Vinayshree
authors.initials: V
authors.lastname: Kumar
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Frost
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Vary
mesh_terms: D000435:Alcoholic Intoxication / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D019893:Ribosomal Protein S6 Kinases