title: 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.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Takegoshi
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.|Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Riuta
authors.initials: R
authors.lastname: Takabatake
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Matsuzawa-Nagata
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shimakami
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shirasaki
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.affiliation: The Tohkai Cytopathology Institute: Cancer Research and Prevention, Gifu, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.|Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D030342:Genetic Diseases, Inborn / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology / Q000517:prevention & control*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D053773:Transforming Growth Factor beta1
keywords: branched-chain amino acids; hepatocellular carcinoma; mammalian target of rapamycin complex 1; nonalcoholic steatohepatitis; transforming growth factor β1