Diet supplementation with soy protein isolate but not the isoflavone genistein protects against alcohol-induced tumor progression in DEN-treated male mice

摘要

In this study, DEN-treated male mice were assigned to 4 groups: a 35% high fat ethanol liquid diet (EtOH), an EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SOY) an EtOH liquid diet supplemented with genistein (EtOH/GEN) and a chow group. EtOH feeding, final concentration 5% (v/v), continued for 16 wks. As expected, EtOH increased both the incidence and multiplicity of both basophilic lesions and adenomas compared to the chow fed group, (p<0.05). Soy protein supplementation in the EtOH/SOY group significantly reduced adenoma progression when compared to the EtOH and EtOH/GEN group, (p<0.05). Genistein supplementation alone in the EtOH diet had no protective effect. In saline-treated mice, soy feeding significantly reduced serum ALT concentrations (p<0.05), decreased hepatic TNFα and CD-14 expression and decreased nuclear accumulation of NFκB protein in the EtOH/SOY-treated mice compared to the EtOH group (p<0.05). With respect to ceramides, high resolution MALDI-FTICR Imaging mass spectrometry revealed changes in the accumulation of long acyl chain ceramide species, in particular C18, in the EtOH group when compared to the EtOH/SOY group. Additionally, expression of the enzymes acid ceramidase and sphingosine kinase 1 which degrade ceramide into sphingosine and convert sphingosine to sphingosine-1-phosphate respectively and expression of sphingosine-1-phosphate receptors S1PR2 and S1PR3 were all upregulated by EtOH and suppressed in the EtOH/SOY group, p<0.05. Chronic EtOH feeding also increased hepatocyte proliferation and mRNA expression of β-catenin targets, including cyclin D1, MMP7 and glutamine synthase, which were reduced in the EtOH/SOY group, p<0.05. These findings suggest that soy prevents tumorigenesis by reducing pro-inflammatory signaling resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of EtOH-mediated β-catenin signaling. These mechanisms may involve blockade of sphingolipid signaling.