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

Abstract

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)

A novel diet‐induced murine model of steatohepatitis with fibrosis for screening and evaluation of drug candidates for nonalcoholic steatohepatitis

“…Long‐term feeding: To determine whether long‐term STHD‐01 feeding can induce liver fibrosis and tumor formation, and whether pretreatment with the carcinogen DEN accelerates the process, C57BL/6J mice were fed with STHD‐01 for 36 weeks, or for 30 weeks with normal drinking water after receiving water containing 0.04% DEN for 10 days prior to initiating STHD‐01 feeding (Ishizaki et al. ). Plasma ALT and hepatic TG were measured at the end of the STHD‐01 feeding period.…”

Increased level of DNA damage in some organs of obese Zucker rats by γ‐H2AX analysis

“…Leptin is encoded by the lep gene and produced by adipocytes [Zhang et al, ], regulating food intake in mammals via a cross‐talk between the adipose tissue and central nervous system that maintains energy balance and normal body weight [Schwartz et al, ]. In addition, as described in the literature, these rats were also used to investigate some mechanisms connected to the obesity‐ or diabetes‐mediated carcinogenesis [Koch et al, ; Ishii et al, ; Ishizaki et al, ; Imai et al, ]. Thus, we aimed to gain information on the obesity‐mediated genotoxic risk by investigating, at tissue level, the expression and time‐course of the γ‐H2AX marker in eight organs of the Zucker rat model.…”

Green Tea Extract Protects Against Diethylnitrosamine‐Mediated Liver Injury And Cell Proliferation By Attenuating STAT3 And iNOS Expression In High Fat‐Induced Obese Mice With Nonalcoholic Steatohepatitis

“…In this thesis, a HFD and DEN were used to not only accelerate HCC development, but reflect symptoms of a NASH-HCC patient, which are increased body mass, insulin resistance, inflammation and fibrosis (74,99). There are different diets in combination with DEN which induces NASH-HCC including Western diet, choline-deficient diet, highsaturated-fat (10% lard oil, 2% cholesterol w/w) and the HFD (60% kcal) (74,100,101). Db/db mice are also commonly used in combination with DEN to illicit NASH-HCC symptoms (10,73).…”