Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis

Muto, Yasutoshi; Sato, Shunichi; Watanabe, Akïharu; Moriwaki, Hisataka; Suzuki, Kazuyuki; Kato, Akinobu; Kato, Masahiko; Nakamura, Teiji; Higuchi, Kenichi; Nishiguchi, Shuhei; Kumada, Hiromitsu; Ohashi, Yasuo

doi:10.1016/j.hepres.2006.04.007

Cited by 156 publications

(230 citation statements)

References 36 publications

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“…Therefore, the findings of the present study, together with the results of previous studies using BCAA (3,4), suggest that improvement of metabolic abnormalities by pharmaceutical or nutritional intervention might be an effective strategy for inhibiting obesity-related liver tumorigenesis.…”

Section: Discussionsupporting

confidence: 72%

“…Finally, it should be emphasized again that prevention of HCC by targeting hepatic steatosis, insulin resistance, and the state of chronic inflammation, which are caused by dysregulation of energy homeostasis, might be one of the promising strategies for the treatment of obese individuals who are at an increased risk of developing HCC (3,4). ACR seems to be potentially effective and critical candidate for this purpose because it can improve hepatic steatosis and insulin resistance while also attenuating chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…The risk factors associated with the development of HCC include chronic hepatitis B and/or hepatitis C infection, particularly with subsequent cirrhosis. Recent evidence also indicates that obesity and the related metabolic abnormalities, especially diabetes mellitus, increase the risk of HCC (1)(2)(3). In a rodent model, the occurrence of diethylnitrosamine (DEN)-induced liver tumorigenesis was found to be significantly higher in obese and diabetic C57BLKS/JþLepr db /þLepr db (db/db) mice than in genetic control mice (4).…”

Section: Introductionmentioning

confidence: 99%

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Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

Shimizu

Sakai

Shirakami

et al. 2011

Cancer Prevention Research

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Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) a due to phosphorylation by Ras/ MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRa, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J-þLepr db /þLepr db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signalregulated kinase) and RXRa proteins in the livers of experimental mice. It also increased the expression of RARb and p21 CIP1 mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRa function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-a and the expression levels of TNF-a, IL-6, and IL-1b mRNA in the livers of DENtreated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

Shimizu

Sakai

Shirakami

et al. 2011

Cancer Prevention Research

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“…21,22 Furthermore, long-term oral supplementation with BCAA granules inhibits liver carcinogenesis in overweight and obese patients with liver cirrhosis. 9 Long-term administration of BCAA improves insulin resistance 15 and inhibits VEGF production, 23 which may therefore inhibit carcinogenesis.…”

Section: Effect Of Branched Chain Amino Acids On Diethylnitrosamine-imentioning

confidence: 99%

“…8 Therefore, we treated Zucker fatty rats with DEN; and then, using this model, we estimated the effect of long-term BCAA administration, which significantly reduced the risk of HCC in cirrhotic patients with a BMI of $25. 9 The mechanism by which BCAA reduces the risk of HCC in cirrhotic patients is not clear; however, Muto et al suggested the effect of BCAA on glucose metabolism may reduce the incidence of liver cancer in cirrhotic patients with a BMI score of 25 or higher, since they may have a particularly higher incidence of hyperinsulinemia and peripheral insulin resistance. This rat model does not develop cirrhosis, but exhibits insulin resistance and hyperinsulinemia; therefore, we selected this model to evaluate tumor suppression by long-term BCAA administration.…”

mentioning

confidence: 99%

Long-term Branched Chain Amino Acid Supplementation Ameliorates Diethylnitrosamine-induced Liver Glutathione S-transferase-p Positivity in Zucker Fatty Rats

Ishizaki

Nishiyama

Hagiwara

2013

Journal of Clinical and Experimental Hepatology

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Background: Obesity increases the risk of fatty liver disease and liver cancer. There are several models of obesityassociated hepatocellular carcinoma, but tumor development in these models is slow. Materials and methods: We investigated Zucker fatty rats, a model of obesity and insulin resistance, to discover if diethylnitrosamine (DEN), a potent liver carcinogen, might enhance liver carcinogenesis. We also investigated the effect of branched chain amino acids (BCAA) against the development of liver cancer. Results: Incidence and number of hepatocellular carcinomas and adenomas were significantly greater in DEN-treated Zucker fatty rats than in DEN-treated lean rats. All treated Zucker fatty rats developed hepatocellular carcinoma within 16 weeks. Long-term BCAA supplementation significantly reduced expression of CyclinD1, PCNA, thymidine kinase, Bcl-2, and GST-p and increased expression of p21 in the liver. Furthermore, BCAA treatment significantly reduced the area of GST-p positive foci. Conclusion: Long-term BCAA treatment may induces cell cycle arrest and apoptotic induction, thus suppressing pre-neoplastic lesions. ( J CLIN EXP HEPATOL 2013;3:192-197)

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Obesity and recurrence‐free survival in patients with hepatocellular carcinoma after achieving sustained virological response to interferon therapy for chronic hepatitis C

Shinkawa

Tanaka

Takemura

et al. 2018

Annals of Gastroent Surgery

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AimSome patients who achieve a sustained virological response (SVR) to interferon (IFN) treatment for chronic hepatitis C prior to hepatic resection for hepatocellular carcinoma (HCC) experience postoperative recurrence. This study investigated the relationship between obesity and postoperative HCC recurrence in SVR patients.MethodsFifty‐nine patients who had achieved SVR before hepatic resection were evaluated. Patients had a solitary tumor ≤5 cm in diameter or ≤3 lesions each ≤3 cm in size with no macroscopic vascular invasion (Milan criteria). Patient characteristics potentially associated with recurrence risk were investigated.ResultsThree‐, 5‐, and 7‐year recurrence‐free survival after surgery were 65%, 44%, and 41%, respectively. Univariate analysis showed that obesity (P < .01), hypertension (P = .038), and non‐anatomical resection (P = .022) were significantly associated with a lower recurrence‐free survival rate. In a multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval [CI] 1.3‐6.1; P < .01) and non‐anatomical resection (hazard ratio, 2.7; 95% CI 1.1‐6.2; P = .025) were independently associated with postoperative recurrence. Three‐, 5‐, and 7‐year overall survival rates after surgery were 100%, 80%, and 64% in obese patients and 100%, 92%, and 82% in non‐obese patients, respectively (P = .014). However, other variables showed no significant difference in the overall survival rate.ConclusionsObesity and non‐anatomical resection were independent risk factors for HCC recurrence after hepatic resection and successful IFN therapy. Obesity is an important clinical problem to consider to improve postoperative outcomes in such patients.

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Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis

Cited by 156 publications

References 36 publications

Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

Long-term Branched Chain Amino Acid Supplementation Ameliorates Diethylnitrosamine-induced Liver Glutathione S-transferase-p Positivity in Zucker Fatty Rats

Obesity and recurrence‐free survival in patients with hepatocellular carcinoma after achieving sustained virological response to interferon therapy for chronic hepatitis C

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