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Title: Liver tumorigenesis is promoted by a high saturated fat diet specifically in male mice and is associated with hepatic expression of the proto-oncogene Agap2 and enrichment of the intestinal microbiome with Coprococcus

Author
item PEDERSEN, KIM - Louisiana State University
item PULLIAM, CASEY - Louisiana State University
item PATEL, AARSHVI - Louisiana State University
item DEL PIERO, FABIO - Louisiana State University
item WATANABE, TATIANE - Louisiana State University
item WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item HICKS, CHINDO - Louisiana State University
item RONIS, MARTIN - Louisiana State University

Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2018
Publication Date: 10/16/2018
Citation: Pedersen, K., Pulliam, C., Patel, A., Del Piero, F., Watanabe, T., Wankhade, U., Shankar, K., Hicks, C., Ronis, M. 2018. Liver tumorigenesis is promoted by a high saturated fat diet specifically in male mice and is associated with hepatic expression of the proto-oncogene Agap2 and enrichment of the intestinal microbiome with Coprococcus. Carcinogenesis. https://doi.org/10.1093/carcin/bgy141.
DOI: https://doi.org/10.1093/carcin/bgy141

Interpretive Summary: Commensal bacteria (microbes) inhabiting the mammalian gut have critical roles in health and disease development. A large body of evidence now exists to support the premise that gut microbial composition strongly influences predisposition to obesity and metabolic disease, including liver dysfunction due to accumulation of fat (non-alcoholic fatty liver disease, NAFLD). Diet composition has a strong influence on the structure and function of the gut microbiome and may contribute to the susceptibility or resilience of individuals toward chronic diseases, including diabetes, obesity and cancer. Studies have shown that dietary fat intake affects the microbiome; however, the effects if dietary fat type on gut microbe-associated changes in liver have not been systematically studied. In this study, C57Bl6/J mice of both sexes were provided ad libitum access to high-fat diets (45% of calories) of varying fat composition (saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats), following a challenge to the liver with a toxin diethyl nitrosamine. Diets containing mono- or PUFA led to significantly lower carcinomas (liver cancers) relative to saturated fat diets. Mice fed different fat types also showed distinct differences in their gut microbial composition and liver gene expression. There was a wide variety of changes in the gut microbiome inclucing the genera SMB53, Allobaculum, and Bifidiobacteriaceae. Coprobacillus and Bifidobacteriaceae were the two genera with the most substantially changes. These findings indicate that dietary fat composition has a robust effect on the gut microbiome, and these dietary fat-associated changes in intestinal bacteria may play important roles in linking dietary patterns to liver function and health.

Technical Abstract: Liver cancer results in a high degree of mortality, especially among men. Since diet-induced fatty liver disease is a risk factor for development of hepatocellular carcinoma (HCC), we investigated the role of dietary fat type in tumor promotion by high fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine (DEN). Tumor incidence and multiplicity was significantly greater in males than in females. In males, the fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in DHA, while carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression several cytochrome P450 enzymes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of Firmicutes and a lower level of genus Akkermansia in males than in females. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affects the gut microbiome, the hepatic transcriptome and hepatic tumor growth.