Oncotarget

Research Papers:

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

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 and Shuichi Kaneko

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Oncotarget. 2017; 8:18191-18205. https://doi.org/10.18632/oncotarget.15304

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Abstract

Kai Takegoshi1, Masao Honda1,2, Hikari Okada1, Riuta Takabatake1, Naoto Matsuzawa-Nagata3, Jean S. Campbell4, Masashi Nishikawa1, Tetsuro Shimakami1, Takayoshi Shirasaki1, Yoshio Sakai1, Taro Yamashita1, Toshinari Takamura3, Takuji Tanaka5, Shuichi Kaneko1,3

1Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

2Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan

3Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

4Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA

5The Tohkai Cytopathology Institute: Cancer Research and Prevention, Gifu, Japan

Correspondence to:

Masao Honda, email: mhonda@m-kanazawa.jp

Keywords: branched-chain amino acids, nonalcoholic steatohepatitis, mammalian target of rapamycin complex 1, hepatocellular carcinoma, transforming growth factor β1

Received: May 12, 2016     Accepted: December 27, 2016     Published: February 13, 2017

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.


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