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Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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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Authors and Affiliations

  1. Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan

    Hitoshi Yoshiji, Ryuichi Noguchi, Mitsuteru Kitade, Kosuke Kaji, Yasuhide Ikenaka, Tadashi Namisaki, Junichi Yoshii, Koji Yanase, Masaharu Yamazaki, Tatsuhiro Tsujimoto, Takemi Akahane, Hideto Kawaratani, Masahito Uemura & Hiroshi Fukui

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  1. Hitoshi Yoshiji
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  2. Ryuichi Noguchi
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Correspondence to Hitoshi Yoshiji.

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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

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