Clofibrate treatment promotes branched-chain amino acid catabolism and decreases the phosphorylation state of mTOR, eIF4E-BP1, and S6K1 in rat liver.
Leucine stimulates protein synthesis by modulating the mammalian target of rapamycin (mTOR) signaling pathway. We hypothesized that promotion of the branched-chain amino acid (BCAA) catabolism might influence the leucine-induced protein synthesis. Clofibric acid (an active metabolite of clofibrate) is known to promote the BCAA catabolism by activation of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), the rate-limiting enzyme of the BCAA catabolism. In the present study, we examined the phosphorylation state of mTOR, eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and ribosomal protein S6 kinase 1 (S6K1) in liver of rats with or without activation of the BCKDC by clofibrate treatment. Clofibrate-treated rats were prepared by oral administration of clofibrate 5 h before sacrifice. In order to stimulate phosphorylation of components in the mTOR signaling pathway, rats were orally administered with leucine 1 h before sacrifice. Clofibrate treatment almost fully activated hepatic BCKDC and significantly decreased the plasma leucine concentration in rats without leucine administration, resulting in decreased mTOR and 4E-BP1 phosphorylation. Similarly, in rats administered with leucine, clofibrate treatment attenuated the predicted increase in plasma leucine concentration as well as the phosphorylation of mTOR, 4E-BP1, and S6K1. These results suggest that BCAA catabolism enhanced by clofibrate treatment has significant influences on the leucine-induced activation of translation initiation processes.
Ishiguro
Hiroki
H
Department of Gastroenterology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Katano
Yoshiaki
Y
Nakano
Isao
I
Ishigami
Masatoshi
M
Hayashi
Kazuhiko
K
Honda
Takashi
T
Goto
Hidemi
H
Bajotto
Gustavo
G
Maeda
Ken
K
Shimomura
Yoshiharu
Y
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002994:Clofibrate / Q000008:administration & dosage / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000597:Amino Acids, Branched-Chain; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D000960:Hypolipidemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C546845:mTOR protein, rat; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat; D058570:TOR Serine-Threonine Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D007930:Leucine; D002994:Clofibrate