A High Fat Diet Supplemented with Soy Prevents Diet Induced Promotion of Liver Tumors in DEN‐Treated Male Mice

Abstract

In the United States, the increase in hepatocellular cancer incidence rates can be partially attributed to increased prevalence of risk factors associated with obesity and metabolic syndrome. Previously we have shown high fat feeding increases tumor progression in DEN‐treated male mice, which was related to hepatic TNFa signaling and macrophage recruitment. In the present study, saline treated and DEN‐treated male mice were fed a 35% high fat liquid diet containing either casein (HF/cas) or soy (HF/soy) as the sole protein source for 16 wks. High fat feeding increased tumor incidence and multiplicity in the HF/cas group compared to the DEN‐treated chow fed group, p<0.05. Soy protein substitution decreased total tumor number which corresponded to reductions in serum ALT concentrations, hepatic steatosis and immune cell infiltration, and nuclear accumulation of NFkB protein in the HF/soy group compared to HF/cas mice , p<0.05. Detection of sphingolipids using high resolution MALDI‐FTICR Imaging mass spectrometry revealed an increase in C18 ceramide and sphingosine 1‐P accumulation in the HF/cas group compared to the HF/soy group. Further analysis demonstrated a significant increase in mRNA expression of ceramide synthase 1 and 4, and in the translocation sphingosine kinase 1 to hepatic microsomal fractions, all of which were ameliorated by soy supplementation. We conclude that soy prevents tumorigenesis in part by reducing the pro‐inflammatory environment by reducing sphingosine 1‐P /NFkB signaling. Supported in part by NCI R21 CA169389 (MJR).