Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

Abstract

Oral supplementation with branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in patients with liver cirrhosis potentially suppresses the incidence of hepatocellular carcinoma (HCC) and improves event-free survival. However, the detailed mechanisms of BCAA action have not been fully elucidated. BCAA were administered to atherogenic and high-fat (Ath+HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice. Liver histology, tumor incidence, and gene expression profiles were evaluated. Ath+HF diet mice developed hepatic tumors at a high frequency at 68 weeks. BCAA supplementation significantly improved hepatic steatosis, inflammation, fibrosis, and tumors in Ath+HF mice at 68 weeks. GeneChip analysis demonstrated the significant resolution of pro-fibrotic gene expression by BCAA supplementation. The anti-fibrotic effect of BCAA was confirmed further using platelet-derived growth factor C transgenic mice, which develop hepatic fibrosis and tumors. In vitro, BCAA restored the transforming growth factor (TGF)-β1-stimulated expression of pro-fibrotic genes in hepatic stellate cells (HSC). In hepatocytes, BCAA restored TGF-β1-induced apoptosis, lipogenesis, and Wnt/β-Catenin signaling, and inhibited the transformation of WB-F344 rat liver epithelial stem-like cells. BCAA repressed the promoter activity of TGFβ1R1 by inhibiting the expression of the transcription factor NFY and histone acetyltransferase p300. Interestingly, the inhibitory effect of BCAA on TGF-β1 signaling was mTORC1 activity-dependent, suggesting the presence of negative feedback regulation from mTORC1 to TGF-β1 signaling. Thus, BCAA induce an anti-fibrotic effect in HSC, prevent apoptosis in hepatocytes, and decrease the incidence of HCC; therefore, BCAA supplementation would be beneficial for patients with advanced liver fibrosis with a high risk of HCC.

Branched-chain amino acid metabolism in cancer

“…Here, BCAT1 controlled cell cycle progression, sustaining breast cancer proliferation. By contrast, Takegoshi et al [ 30 ] suggested that BCAAs prevented development of hepatocellular carcinoma in mice models of nonalcoholic steatohepatitis. As in the studies described above, BCAAs appeared to act via mTORC1.…”

Leucine‐rich diet minimises liver glycogen mobilisation and modulates liver gluconeogenesis enzyme expression in tumour‐bearing cachectic rats

“…Leucine efficiently improves skeletal muscle protein synthesis in patients [17, 18] and in animals, as shown previously [19–22]. Leucine alone and in a complete BCAA mixture stimulates protein synthesis and decreases protein proteolysis [23–25]. Leucine regulates protein synthesis in the skeletal muscle following food intake, stimulating the mTOR pathway and inhibiting the ubiquitin‐proteasome pathway [23, 26].…”

“…Leucine regulates protein synthesis in the skeletal muscle following food intake, stimulating the mTOR pathway and inhibiting the ubiquitin‐proteasome pathway [23, 26]. Moreover, a recent study performed by Takegoshi and colleagues [25] revealed that oral BCAA supplementation in patients with liver cirrhosis potentially suppresses the incidence of hepatocellular carcinoma, inducing anti‐fibrotic factors and preventing apoptosis.…”

Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic Steatohepatitis

“…In addition, our observation might explain why mTORC1 activation by branched-chain amino acids prevents hepatic fibrosis and HCC development in NASH. 49 Our data open up the potential for macrophage mTORC1 as a target for lessening liver inflammation and halting the progression of NASH.…”