Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system.
The administration of branched-chain amino acids (BCAAs) to cirrhosis patients increases serum albumin levels and improves the blood Fischer's ratio. Although it has been reported that albumin synthesis in rat primary hepatocytes is diminished under lower Fisher's ratio conditions compared to normal Fischer's ratio conditions, the mode of action at the molecular level for these effects is still uncertain. It has been reported recently that the triggering signal for protein synthesis is transmitted through mTOR (mammalian target of rapamycin). We have had an interest in the mTOR signal transduction system. In the present study, we analyzed the mode of action of BCAA-induced albumin synthesis using rat primary hepatocytes. The BCAA mixture dose-dependently promoted the production of albumin, with leucine being the major effector half of which was inhibited by the mTOR inhibitor rapamycin. We also showed that only leucine induces P70 S6 kinase activation and 4E-BP1 phosphorylation which are mTOR's downstream translational effectors. These activations were completely inhibited by rapamycin. Our results suggest that BCAAs, especially leucine, promote the production of albumin in rat primary hepatocytes through an mTOR signal transduction system.
Ijichi
Chiori
C
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan. chiori_ijichi@ajinomoto.com
Matsumura
Tsuyoshi
T
Tsuji
Takashi
T
Eto
Yuzuru
Y
D000418:Albumins / Q000737:chemistry* / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism*; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007532:Isoleucine / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014633:Valine / Q000378:metabolism
D000418:Albumins; D000597:Amino Acids, Branched-Chain; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D007532:Isoleucine; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D014633:Valine; D020123:Sirolimus