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.

Exercise and diet in the management of nonalcoholic fatty liver disease

“…In proof of concept studies, mice fed a diet high in trans fats and high fructose com syrup for 16 weeks developed hyperinsulinemia and severe hepatic necroinflammation [48); when trans fats were eliminated, steatohepatitis improved [49] . Animal models also suggest a role for HCC development with high intake of dietary trans fats and high fructose com syrup [50). Overall, data from human epidemiologic studies and animal models [51) support eliminating trans fats from the human diet, and further ·data are unlikely to change this recommendation given that randomized trials are unethical.…”

Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions

“…indicated by less enhanced gene expression of enzymes (acetyl CoA carboxylase and fatty acid synthase) in a similar model of NASH-HCC for 1 year duration. 36 The discrepancy between less necroptotic activity and progressive fibrosis at the late stage may result from fibrotic influence and is seen in other models of severe fibrosis/cirrhosis, such as carbon tetrachloride (CCl 4 ) or thioacetamide (TAA) intoxication. 11 Hyperplastic nodules are indicative of aberrant proliferation of hepatocytes, and were seen with dysplasia in some of mice.…”

Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kB or Akt/mTORC1

“…The earlier onset and more aggressive nature of DEN-induced HCC with obesity and diabetes were supported by the high rate of pulmonary metastases at 9 mths, 60% in obese vs. 10% in lean Wt mice. Others have used genetic (leptin or leptin receptor defective) and dietary models to show that obesity enhances DEN-induced hepatocarcinogenesis [4,33,34]. In foz/foz mice, such accelerated onset of HCC is associated with hyperinsulinemia, diabetes, hyperleptinemia, hypoadiponectinemia and fatty liver, all relevant to the metabolic complications of human obesity.…”