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Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

Cha JH, Bae SH, Kim HL, Park NR, Choi ES, Jung ES, Choi JY, Yoon SK - PLoS ONE (2013)

Bottom Line: 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 BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Purpose: 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.

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Effects of BCAA supplementation on angiogenesis in rats after 16 weeks of DEN administration.The relative band intensities of the angiogenesis markers are shown in the right-hand panels (A). The expression level of Tie-2 mRNA was determined by RT-PCR (B). VEGF protein expression was determined by Western blotting (C). The expression level of each gene is normalized to those of GAPDH (A and B) and β-actin (C). The lanes contain mRNA (A) and protein (C) samples from three rats per group. Values shown are means ± standard deviation. *P<0.05.
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pone-0077899-g004: Effects of BCAA supplementation on angiogenesis in rats after 16 weeks of DEN administration.The relative band intensities of the angiogenesis markers are shown in the right-hand panels (A). The expression level of Tie-2 mRNA was determined by RT-PCR (B). VEGF protein expression was determined by Western blotting (C). The expression level of each gene is normalized to those of GAPDH (A and B) and β-actin (C). The lanes contain mRNA (A) and protein (C) samples from three rats per group. Values shown are means ± standard deviation. *P<0.05.

Mentions: The BCAA groups showed downregulated expression of mRNA for angiogenesis markers (VEGF, Tie-2, HIF-1α) and apoptosis inhibitor markers (Mcl-1, cIAP-1) at 16 weeks of DEN administration, as compared to the corresponding levels in the casein group. Significant decreases in the levels of mRNA for VEGFA (6% BCAA; P<0.05), Tie-2, HIF-1α (3% and 6% BCAA; P<0.05), Mcl-1 (6% BCAA; P<0.05), and cIAP-1 (3% and 6% BCAA; P<0.05) were observed in the BCAA groups, as compared to the casein group (Figs. 4A and 5A). Similarly, quantitative Real-Time RT-PCR showed that BCAA treatment resulted in significant decreases in the levels of mRNA for Tie-2 and cIAP-1 (3% and 6% BCAA; P<0.05), as compared to the casein group (Figs. 4B and 5B).


Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

Cha JH, Bae SH, Kim HL, Park NR, Choi ES, Jung ES, Choi JY, Yoon SK - PLoS ONE (2013)

Effects of BCAA supplementation on angiogenesis in rats after 16 weeks of DEN administration.The relative band intensities of the angiogenesis markers are shown in the right-hand panels (A). The expression level of Tie-2 mRNA was determined by RT-PCR (B). VEGF protein expression was determined by Western blotting (C). The expression level of each gene is normalized to those of GAPDH (A and B) and β-actin (C). The lanes contain mRNA (A) and protein (C) samples from three rats per group. Values shown are means ± standard deviation. *P<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815299&req=5

pone-0077899-g004: Effects of BCAA supplementation on angiogenesis in rats after 16 weeks of DEN administration.The relative band intensities of the angiogenesis markers are shown in the right-hand panels (A). The expression level of Tie-2 mRNA was determined by RT-PCR (B). VEGF protein expression was determined by Western blotting (C). The expression level of each gene is normalized to those of GAPDH (A and B) and β-actin (C). The lanes contain mRNA (A) and protein (C) samples from three rats per group. Values shown are means ± standard deviation. *P<0.05.
Mentions: The BCAA groups showed downregulated expression of mRNA for angiogenesis markers (VEGF, Tie-2, HIF-1α) and apoptosis inhibitor markers (Mcl-1, cIAP-1) at 16 weeks of DEN administration, as compared to the corresponding levels in the casein group. Significant decreases in the levels of mRNA for VEGFA (6% BCAA; P<0.05), Tie-2, HIF-1α (3% and 6% BCAA; P<0.05), Mcl-1 (6% BCAA; P<0.05), and cIAP-1 (3% and 6% BCAA; P<0.05) were observed in the BCAA groups, as compared to the casein group (Figs. 4A and 5A). Similarly, quantitative Real-Time RT-PCR showed that BCAA treatment resulted in significant decreases in the levels of mRNA for Tie-2 and cIAP-1 (3% and 6% BCAA; P<0.05), as compared to the casein group (Figs. 4B and 5B).

Bottom Line: 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 BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Purpose: 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.

Show MeSH
Related in: MedlinePlus