Diet-induced Hepatocellular Carcinoma in Genetically Predisposed Mice.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with ~70% of cases resulting from hepatitis B and C infections, aflatoxin exposure, chronic alcohol use, or genetic liver diseases. The remaining ~30% of cases are associated with obesity, type 2 diabetes, and related metabolic diseases although a direct link has not been established. We tested the long‐term (~500 days) effects of high‐fat and low‐fat diets on two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to NASH (non‐alcoholic steatohepatitis) and HCC on a high fat but not low fat diet. Susceptible mice showed characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia, and HCC. mRNA profiles of HCCs versus livers showed involvement of two networks, one centered on Myc and the other on NFKB, a result that is consistent with the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment and differential expression of miR‐146 that is involved in NFKB signaling. A switch from high‐fat to low‐fat diet reversed the outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. This demonstrates that diet modification has important implications for the prevention of HCC.