title: Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice.
abstract: Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.
authors.affiliation: Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Iwasa
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiraki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Terakura
authors.forename: Koji
authors.initials: K
authors.lastname: Takai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage*; D000818:Animals; D048909:Diabetes Complications / Q000517:prevention & control*; D019587:Dietary Supplements; D004052:Diethylnitrosamine / Q000633:toxicity; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*
chemical_list: D000597:Amino Acids, Branched-Chain; D020738:Leptin; D004052:Diethylnitrosamine; D000410:Alanine Transaminase