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.

• Authors: Kai Takegoshi, Masao Honda, Hikari Okada, Riuta Takabatake, Naoto Matsuzawa-Nagata, Jean S Campbell, Masashi Nishikawa, Tetsuro Shimakami, Takayoshi Shirasaki, Yoshio Sakai, Taro Yamashita, Toshinari Takamura, Takuji Tanaka, Shuichi Kaneko
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 11 Pg. 18191-18205 (Mar 14 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28212548 (Publication Type: Journal Article)

Chemical References

• Amino Acids, Branched-Chain
• Transforming Growth Factor beta1

Topics

• Amino Acids, Branched-Chain (pharmacology)
• Animals
• Carcinoma, Hepatocellular (pathology, prevention & control)
• Disease Models, Animal
• Genetic Diseases, Inborn (pathology, prevention & control)
• Humans
• Liver Cirrhosis (pathology, prevention & control)
• Liver Neoplasms (etiology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (pathology, prevention & control)
• Transforming Growth Factor beta1 (metabolism)