title: Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice.
abstract: Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.
authors.affiliation: Department of Gastroenterology,  Gifu University Graduate School of Medicine, Gifu 501-1194,  Japan.
authors.forename: Daishi
authors.initials: D
authors.lastname: Terakura
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Junpei
authors.initials: J
authors.lastname: Iwasa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Baba
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kochi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiraki
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: D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage*; D000818:Animals; D016207:Cytokines / Q000235:genetics; D019587:Dietary Supplements; D007333:Insulin Resistance; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047495:PPAR gamma / Q000235:genetics; D011230:Precancerous Conditions / Q000276:immunology / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000597:Amino Acids, Branched-Chain; D016207:Cytokines; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger