title: Hepatocellular proliferation and hepatocarcinogen bioactivation in mice with diet-induced fatty liver and obesity.
abstract: Human liver cancer is in part associated with obesity and related metabolic diseases. The present study was undertaken in a mouse model of diet-induced obesity (DIO) and hepatic steatosis, conditions which can be associated with hepatic neoplasia, to determine whether the rates of cell proliferation or hepatocarcinogen bioactivation were altered in ways which could facilitate hepatocarcinogenesis. DIO mice were generated by feeding C57BL/6 (B6) male mice a high-fat diet beginning at 4 weeks of age; age-matched conventional lean (LEAN) B6 mice fed a low fat diet (10% Kcal from fat) were used for comparison. Groups of 28 week old DIO and LEAN mice were dosed with the bioactivation-dependent DNA-reactive hepatocarcinogen 2-acetylaminofluorene (AAF), at 2.24 or 22.4 mg/kg, given by gavage 3 times per week for 31 days, or received no treatment (DIO and LEAN control groups). Compared with the LEAN control group, the DIO control group had a higher mean body weight (16.5 g), higher mean absolute (1.4 g) and mean relative (25.5%) liver weights, higher (394%) liver triglyceride concentrations, and an increased incidence and severity of hepatocellular steatosis at the end of the dosing phase. The DIO control group also had a higher mean hepatocellular replicating fraction (31% increase, determined by proliferating cell nuclear antigen immunohistochemistry). Hepatocarcinogen bioactivation, based on formation of AAF DNA adducts as measured by nucleotide (32)P-postlabeling, was similar in both DIO and LEAN AAF-dosed groups. Thus, hepatocellular proliferation, but not hepatocarcinogen bioactivation, was identified as an alteration in livers of DIO mice which could contribute to their susceptibility to hepatocarcinogenesis.
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Iatropoulos
authors.forename: J-D
authors.initials: JD
authors.lastname: Duan
authors.forename: A M
authors.initials: AM
authors.lastname: Jeffrey
authors.forename: M W
authors.initials: MW
authors.lastname: Leach
authors.forename: A N
authors.initials: AN
authors.lastname: Hayes
authors.forename: N L
authors.initials: NL
authors.lastname: Stedman
authors.forename: G M
authors.initials: GM
authors.lastname: Williams
mesh_terms: D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives / Q000633:toxicity; D000821:Animal Feed; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects*; D018736:DNA Adducts / Q000032:analysis / Q000096:biosynthesis; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000503:physiopathology*; D022781:Hepatocytes / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000503:physiopathology
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D015073:2-Acetylaminofluorene