Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.
OBJECTIVE
Recent studies have revealed that branched-chain amino acids (BCAA) reduce the development of hepatocellular carcinoma (HCC) in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR). The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN)-induced HCC and liver cirrhosis in a rat model.


METHODS
Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight) for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting.


RESULTS
The mean area and number of dysplastic nodules (DNs) and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression.


CONCLUSIONS
BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.
The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Republic of Korea ; Department of Internal Medicine College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Jung Hoon
JH
Cha
Si Hyun
SH
Bae
Hye Lim
HL
Kim
Na Ri
NR
Park
Eun Suk
ES
Choi
Eun Sun
ES
Jung
Jong Young
JY
Choi
Seung Kew
SK
Yoon
D000284:Administration, Oral; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D063646:Carcinogenesis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004052:Diethylnitrosamine; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden
D000597:Amino Acids, Branched-Chain; D016588:Anticarcinogenic Agents; D004052:Diethylnitrosamine