Abstract 2413: Diet-induced non-alcoholic steatohepatitis and hepatocellular carcinoma in chromosome substitution strains of mice

Abstract

Abstract Hepatocellular Carcinoma (HCC) is the 5th most common cancer worldwide, with increased risk occurring in patients with hepatitis C and B, alcoholism, aflatoxin, and metabolic diseases. Animal models that target liver cells with chemical, physical or biological agents are useful for understanding molecular pathways, but do not capture the natural development of liver cancer through gene-environment interactions. By contrast, several inbred strains of mice have been used to study these interactions in diet-induced metabolic diseases. In particular, C57BL/6J (B6) inbred mice are susceptible to diet-induced obesity, lipid disorders and insulin resistance, whereas A/J mice produce no signs of these diet-induced conditions. In these inbred models, the action of many genes and gene-environment interactions more closely reflect the usual features in non-alcoholic steatohepatitis (NASH) and HCC pathogenesis. Previous studies showed that B6 males are susceptible to diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). We therefore examined the long-term effects of a high fat (HF) diet versus a low fat (LF) diet in males from two inbred strains A/J and B6 to determine whether conditions associated with risk factors ultimately transition to HCC. On the HF diet, A/J males remained lean and were resistant to NASH, whereas B6 males were obese and showed histological and biochemical features of NASH, and in many cases NASH progressed to HCCs with molecular and histological features that were remarkably similar to those reported for the two major HCC classes in humans. On the LF diet, both A/J and B6 were resistant to NASH and HCC. Messenger RNA profiles of HCCs versus tumor-free livers implicated two signaling networks, one centered on Myc and the other on NFκB. Also, we tested whether long-term exposure to the HF diet would give the same response in Chromosome Substitution Strains (CSSs) as with the parental strains. The B6-ChrA/J CSS panel consists of 22 mouse strains in which each CSS consist of a single substituted chromosome from a donor strain (A/J) onto the background of a host strain (B6). We found that most CSSs were resistant to diet-induced obesity, matching their A/J parent, with a few resembling the obesity of the B6 parental strain. We selected two strains from the CSS panel, B6-Chr18A/J which shows diet-induced obesity, and B6-Chr5A/J, an obesity resistant strain, to test long-term HF diet effects. Although initially lean during short-term HF diet tests, B6-Chr5A/J eventually became obese and showed a strong susceptibility to NASH and HCC. By contrast, B6-Chr18A/J remained obese throughout the long-term study, but remarkably maintained features of a normal liver, showed a greatly reduced susceptibility to NASH, and complete resistance to HCC. These studies show that complex interactions between genetic and dietary factors modulate susceptibility to liver disease and cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2011-2413