title: Obesity, but not ethanol, promotes tumor incidence and progression in a mouse model of hepatocellular carcinoma in vivo.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is a major global health burden. Although chronic, heavy alcohol abuse is an established risk factor for HCC, obesity is emerging as an increasingly important factor in HCC development. Given that other risk factors for HCC act synergistically to promote tumorigenesis, we investigated the effects of diet-induced obesity and chronic ethanol consumption on tumor progression.
  
  
  METHODS
  A diethylnitrosamine (DEN) mouse model of HCC was established and mice randomized to control (CD; 10 % kcal% fat) or high fat (HFD; 60 % kcal% fat diet) at 5 weeks of age. At 35 weeks, mice were randomized to 10/20 % ethanol (EtOH) in drinking water (alternate days), or drinking water (H2O) alone. Tumor incidence/size were measured and confirmed. Liver tissue was analyzed for oxidative stress and EtOH-metabolizing enzymes and serum analyzed for liver function and nutritional status.
  
  
  RESULTS
  DEN treatment induced HCC formation in 60 % CD-H2O mice (6 of 10), an effect exacerbated by HFD (89 %). Tumors in HFD animals occupied significantly more of the liver than mice on CD. EtOH-feeding did not impact HCC incidence or tumor size. HFD resulted in increased liver injury and liver:body weight ratio regardless of EtOH consumption. Increased tumor incidence was associated with elevated hepatic oxidative stress in the absence of changes in intrinsic antioxidant (glutathione) levels.
  
  
  CONCLUSIONS
  Obesity independently promoted HCC formation in the absence or presence of a known hepatocarcinogen (DEN), and enhanced both number and size of hepatic tumors independent of chronic EtOH consumption in mice.
authors.affiliation: Department of General Surgery, Hepatobiliary and Pancreatic Surgery, Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 300, Charlotte, NC 28203, USA. kyle.thompson@carolinas.org
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Thompson
authors.forename: Ryan Z
authors.initials: RZ
authors.lastname: Swan
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Walling
authors.forename: David A
authors.initials: DA
authors.lastname: Iannitti
authors.forename: Iain H
authors.initials: IH
authors.lastname: McKillop
authors.forename: David
authors.initials: D
authors.lastname: Sindram
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology; D045744:Cell Line, Tumor; D002492:Central Nervous System Depressants / Q000494:pharmacology; D018450:Disease Progression; D000431:Ethanol / Q000494:pharmacology*; D015994:Incidence; D008113:Liver Neoplasms; D008114:Liver Neoplasms, Experimental / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications*; D012307:Risk Factors
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol