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

• Published in: Carcinogenesis (New York) 2019-04, Vol.40 (2), p.349-359
• Main Authors: Pedersen, Kim B, Pulliam, Casey F, Patel, Aarshvi, Del Piero, Fabio, Watanabe, Tatiane T N, Wankhade, Umesh D, Shankar, Kartik, Hicks, Chindo, Ronis, Martin J
• Format: Article
• Language: English
• Subjects: Animals; Bile Acids and Salts - metabolism; Carcinogenesis; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - microbiology; Carcinoma, Hepatocellular - pathology; Diet, High-Fat - adverse effects; Dietary Fats - adverse effects; Docosahexaenoic Acids - pharmacology; Fatty Acids - metabolism; Female; Gastrointestinal Microbiome - physiology; GTP-Binding Proteins - metabolism; Lipid Metabolism - physiology; Liver - metabolism; Liver - microbiology; Liver - pathology; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - microbiology; Liver Neoplasms - pathology; Male; Mice; Mice, Inbred C57BL; Proto-Oncogenes - physiology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgy141

Abstract Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, 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. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas 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 of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth. In a mouse model of liver tumor promotion, a diet high in saturated fat promoted tumorigenesis more than a low-fat diet or diets high in mono- or polyunsaturated fats specifically in males.