Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice

Pulliam

Pedersen

et al. 2017

Exp Biol Med (Maywood)

Self Cite

The impact of dietary components on cancer is a topic of great interest for both the general public and the scientific community. Liver cancer is currently the second leading form of cancer deaths worldwide. Our study has addressed the effect of the protein source on hepatic tumor promotion in a mouse model reflecting aspects of non-alcoholic fatty liver disease (NAFLD). A high-fat liquid diet with casein as the protein source promotes hepatic injury and tumor promotion in diethylnitrosamine-treated mice. Replacing casein with a soy protein isolate led to a pronounced diminishment of tumor promotion and associated hepatic injury and inflammation. The study thus demonstrates that a dietary protein source can have beneficial, preventative effects on hepatic tumor promotion. AbstractAlcoholic and nonalcoholic fatty liver diseases are risk factors for development of hepatocellular carcinoma, but the underlying mechanisms are poorly understood. On the other hand, ingestion of soy-containing diets may oppose the development of certain cancers. We previously reported that replacing casein with a soy protein isolate reduced tumor promotion in the livers of mice with alcoholic liver disease after feeding a high fat ethanol liquid diet following initiation with diethylnitrosamine. Feeding soy protein isolate inhibited processes that may contribute to tumor promotion including inflammation, sphingolipid signaling, and Wnt/b-catenin signaling. We have extended these studies to characterize liver tumor promotion in a model of nonalcoholic fatty liver disease produced by chronic feeding of high-fat liquid diets in the absence of ethanol. Mice treated with diethylnitrosamine on postnatal day 14 were fed a high-fat liquid diet made with casein or SPI as the sole protein source for 16 weeks in adulthood. Relative to mice fed normal chow, a high fat/casein diet led to increased tumor promotion, hepatocyte proliferation, steatosis, and inflammation. Replacing casein with soy protein isolate counteracted these effects. The high fat diets also resulted in a general increase in transcripts for Wnt/b-catenin pathway components, which may be an important mechanism, whereby hepatic tumorigenesis is promoted. However, soy protein isolate did not block Wnt signaling in this nonalcoholic fatty liver disease model. We conclude that replacing casein with soy protein isolate blocks development of steatosis, inflammation, and tumor promotion in diethylnitrosamine-treated mice fed high fat diets.

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 57%

“…10,11 The liquid diets were purchased from Dyets Inc., Bethlehem, PA. The protein source in the liquid diets was either casein (CAS) (n ¼ 22) or SPI (n ¼ 23).…”

Section: Experimental Animalsmentioning

confidence: 99%

“…10 Steatosis and inflammation were scored as reported earlier. 15 The pathologists were blinded to the treatment groups.…”

Section: Liver Pathologymentioning

confidence: 99%

See 2 more Smart Citations

Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet

Pulliam

Pedersen

et al. 2017

Exp Biol Med (Maywood)

Self Cite

“…Liver (∼100 mg) and feces (∼50 mg) lipids were extracted by chloroform:isopropanol:NP-40 (7:11:0.1), and total, free, and esterified cholesterol concentrations were measured by using a commercially available assay (ab65359; Abcam). Nuclear and membrane protein fractions were obtained as previously described (29). Proteins (30 μg) were separated by SDS-PAGE by standard methods.…”

Section: Serum Biochemistry After Being Killed Blood Was Collectedmentioning

confidence: 99%

Infant Formula Feeding Increases Hepatic Cholesterol 7α Hydroxylase (CYP7A1) Expression and Fecal Bile Acid Loss in Neonatal Piglets

The Journal of Nutrition

Bhattacharyya

Díaz-Rubio

et al. 2018

Diet Supplementation with Soy Protein Isolate, but Not the Isoflavone Genistein, Protects Against Alcohol-Induced Tumor Progression in DEN-Treated Male Mice

Advances in Experimental Medicine and Biology

Pulliam

Hennings

et al. 2018

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.