title: Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle.
abstract: Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Dowman
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom. Electronic address: ljh2g13@soton.ac.uk.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Hopkins
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikolaou
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Armstrong
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shaw
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Diarmaid D
authors.initials: DD
authors.lastname: Houlihan
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.affiliation: Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hübscher
authors.affiliation: Department of NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. Electronic address: p.n.newsome@bham.ac.uk.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000150:complications* / Q000473:pathology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005632:Fructose / Q000009:adverse effects*; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D009765:Obesity / Q000150:complications / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000378:metabolism; D057185:Sedentary Behavior; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000473:pathology
chemical_list: D007328:Insulin; D055758:SOX9 Transcription Factor; D005632:Fructose