title: Tissue-specific regulation of 4E-BP1 and S6K1 phosphorylation by alpha-ketoisocaproate.
abstract: The indispensable branched-chain amino acid leucine acts as a key regulator of mRNA translation by modulating the phosphorylation of proteins that represent important control points in translation initiation, including the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (S6K1). In the current study, we compared the effects of L- and D-enantiomers of leucine on the phosphorylation of 4E-BP1 and S6K1. We also assessed whether leucine itself or its metabolite, alpha-ketoisocaproate (alpha-KIC), mediates the effects of leucine. Food-deprived (18 h) rats were orally administered 135 mg/100 g body weight L-leucine, D-leucine or alpha-KIC and were sacrificed after 1 h. L-Leucine administration had an obvious stimulatory effect on the phosphorylation of 4E-BP1 and S6K1 in both skeletal muscle and liver while D-leucine was much less effective, indicating that the effect of leucine is stereospecific. Oral administration of alpha-KIC mimicked the stimulatory effect of L-leucine in skeletal muscle. In contrast to skeletal muscle, provision of alpha-KIC was significantly less effective than L-leucine in the liver. The results showing that the efficacy of L-leucine and alpha-KIC in stimulating phosphorylation of S6K1 and 4E-BP1 is equivalent in skeletal muscle, may be explained by the conversion of alpha-KIC to L-leucine.
authors.affiliation: Department of Animal Science, Utsunomiya University, 350 Mine-machi, Utsunomiya, Tochigi 321-8505, Japan. fumiaki@cc.utsunomiya-u.ac.jp
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yoshizawa
authors.forename: Haruhito
authors.initials: H
authors.lastname: Sekizawa
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Hirayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005508:Food Deprivation; D047908:Intracellular Signaling Peptides and Proteins; D007532:Isoleucine / Q000097:blood; D007651:Keto Acids / Q000378:metabolism / Q000494:pharmacology*; D007930:Leucine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D013237:Stereoisomerism; D014633:Valine / Q000097:blood
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007651:Keto Acids; D010750:Phosphoproteins; D007532:Isoleucine; C013082:alpha-ketoisocaproic acid; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat; D007930:Leucine; D014633:Valine