Abstract
Background
Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). However, the possible mechanism is still obscure. The aim of the present study was to examine the effect of BCAAs, especially in conjunction with angiogenesis, on hepatocarcinogenesis under the condition of IR.
Methods
The effect of BCAAs on the development of liver enzyme-altered preneoplastic lesions and angiogenesis was examined in obese diabetic Otsuka Long-Evans Tokushima Fatty rats. We also performed an in vitro study to elucidate the possible mechanisms involved.
Results
Treatment with BCAAs markedly inhibited glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of neovascularization in the liver. The hepatic expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, was also attenuated. BCAA treatment significantly suppressed glucose- and insulin-induced in vitro angiogenesis in the presence of VEGF.
Conclusions
In obese diabetic rats BCAAs exerted a chemopreventive effect against HCC, associated with the suppression of VEGF expression and hepatic neovascularization. Since BCAA preparations are widely used in clinical practice for patients with chronic liver diseases, this agent may represent a new strategy for chemoprevention against HCC in the future.
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Abbreviations
- ALT:
-
Alanine aminotransferase
- BCAA:
-
Branched-chain amino acid
- CHC:
-
Chronic hepatitis C
- DEN:
-
Diethylnitrosamine
- DM:
-
Diabetes mellitus
- EC:
-
Endothelial cells
- GST-P:
-
Glutathione-S-transferase placental form
- HCC:
-
Hepatocellular carcinoma
- HCV:
-
Hepatitis virus C
- HUVEC:
-
Human umbilical vein endothelial cells
- IR:
-
Insulin resistance
- LETO:
-
Long-Evans Tokushima Otsuka rats
- MAb:
-
Neutralizing monoclonal antibody
- mTOR:
-
Mammalian target of rapamysin
- NASH:
-
Non-alcoholic steatohepatitis
- OLETF:
-
Otsuka Long-EvansTokushima Fatty rats
- PH:
-
Partial hepatectomy
- QUICKI:
-
Quantitative insulin sensitivity check index
- VEGF:
-
Vascular endothelial growth factor
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Yoshiji, H., Noguchi, R., Kitade, M. et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 44, 483–491 (2009). https://doi.org/10.1007/s00535-009-0031-0
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DOI: https://doi.org/10.1007/s00535-009-0031-0