Oral administration of branched-chain amino acids activates the mTOR signal in cirrhotic rat liver

BCAA granules (a mixture of branched-chain amino acids) have been used to reverse the hypoalbuminemia of decompensated liver cirrhotic patients in Japan. Our previous studies showed that BCAA promoted albumin secretion through the mTOR signal transduction pathway in rat primary hepatocyte culture [Ijichi C, Matsumura T, Tsuji T, Eto Y. Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system. Biochem Biophys Res Commun 2003;303:59-64]. However, the mTOR-activating effect of BCAA in the experimental cirrhotic animals presenting with hypoalbuminemia has not yet been examined. The purpose of this study is to assess whether oral administration of BCAA induces mTOR activity in the livers of normal rats and CCl4-induced cirrhotic rats (CCl4 rats). Biochemical analysis of liver extracts isolated from several rats showed that oral administration of BCAA (0.75 g/kg body weight (BW)) induced phosphorylation of 4E-BP1 and stimulated the enzymatic activity of p70 S6K. Both of these molecules act downstream of mTOR. From the results, we conclude that orally administrated BCAA augments albumin synthesis in the liver, not only by supplementation of material substrates for protein synthesis, but also by induction of an mTOR signal that is critical for translational initiation. Furthermore, we conclude that induction of mTOR signaling is one of the major pharmacological mechanisms by which BCAA granules reverse the hypoalbuminemia of cirrhotic patients.