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.
Highlights
The recent increase in non-alcoholic fatty liver disease (NAFLD) associated with metabolic syndrome could represent a high risk factor for hepatocellular carcinoma (HCC) [1]
The area of fibrosis deduced from densitometry analysis and the hydroxyproline content in the liver revealed the progression of hepatic fibrosis from 38w to 68w, and hepatic fibrosis was significantly reduced in the atherogenic combined with high-fat (Ath+HF)+branched-chain amino acids (BCAA) group compared with the Ath+HF group (Figure 1C and 1D)
Laboratory data for the serum of 12w and 68w mice (Supplementary Table 1) showed that the levels of serum alanine aminotransferase (ALT), plasma total cholesterol, and free cholesterol were significantly upregulated in the Ath+HF group compared with the basal diet group, and the values were significantly reduced in the Ath+HF+BCAA group in 68w mice
Summary
The recent increase in non-alcoholic fatty liver disease (NAFLD) associated with metabolic syndrome could represent a high risk factor for HCC [1]. The development of hepatic steatosis associated with inflammatory changes, called non-alcoholic steatohepatitis (NASH), can lead to liver cirrhosis and hepatocellular www.impactjournals.com/oncotarget carcinoma (HCC). The lack of an appropriate experimental model of HCC that develops on a background of NASH could be a barrier to the development of effective therapies for preventing and treating NASH-derived HCC. To address these limitations, we previously reported an atherogenic combined with high-fat (Ath+HF) diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and insulin resistance [2].
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