Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model.
Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model.
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DOI：
10.18632/oncotarget.15304
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Kaneko S
中科院分区：
文献类型：
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作者：
Takegoshi K;Honda M;Okada H;Takabatake R;Matsuzawa-Nagata N;Campbell JS;Nishikawa M;Shimakami T;Shirasaki T;Sakai Y;Yamashita T;Takamura T;Tanaka T;Kaneko S
肝硬化患者口服补充支链氨基酸（BCAA、亮氨酸、异亮氨酸和缬氨酸）可能抑制肝细胞癌（HCC）的发病率，并提高无事件生存期。然而，BCAA作用的详细机制尚未完全阐明。BCAA被给予致动脉粥样硬化和高脂肪（Ath+HF）饮食诱导的非酒精性脂肪性肝炎（NASH）模型小鼠。评估肝脏组织学、肿瘤发生率和基因表达谱。Ath+HF饮食小鼠在68周时发生肝脏肿瘤的频率很高。68周时，补充BCAA可显著改善Ath+HF小鼠的肝脂肪变性、炎症、纤维化和肿瘤。基因芯片分析显示，补充BCAA显著降低了促纤维化基因的表达。用转血小板源性生长因子C的小鼠进一步证实了BCAA的抗纤维化作用，这些小鼠发生肝纤维化和肿瘤。在体外，BCAA恢复了转化生长因子(TGF)-β1刺激的肝星状细胞（HSC）促纤维化基因的表达。在肝细胞中，BCAA恢复TGF-β1诱导的凋亡、脂肪生成和Wnt/β-Catenin信号通路，抑制WB-F344大鼠肝上皮干细胞样细胞的转化。BCAA通过抑制转录因子NFY和组蛋白乙酰转移酶p300的表达来抑制tgf - β 1r1的启动子活性。有趣的是，BCAA对TGF-β1信号传导的抑制作用依赖于mTORC1的活性，提示mTORC1对TGF-β1信号传导存在负反馈调节。因此，BCAA在HSC中诱导抗纤维化作用，防止肝细胞凋亡，降低HCC的发生率；因此，补充支链氨基酸对HCC高风险的晚期肝纤维化患者是有益的。
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.