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

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.

Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma

“…The findings that are different here from previous studies are: 1) decrease in Bifidobacterium for all stages but less of a decrease seen for HCC, 2) the occurrence of another proinflammatory bacteria, Dorea which increases with stage of CLD (Leclercq et al, 2014), 3) the appearance of increased Coprococcus, a pro-inflammatory bacteria associated with western HFD which increases in CHB and LC but decreases in abundance in HCC (Pedersen et al, 2019), and 4) the decrease in Roseburia, an organism that cross-feeds other beneficial bacteria via it ability to degrade dietary β-mannans, with increasing disease stage (La Rosa et al, 2019).…”

Pregnancy and diet-related changes in the maternal gut microbiota following exposure to an elevated linoleic acid diet

“…In response to the HLA diet, we not only observed decreased abundance of Akkermansia but also of Sutterella, and increased abundance of Butyricimonas and Coprococcus. Alterations in the abundances of these bacteria in response to increased dietary lipid intake have been reported previously (3,26,32), indicating that all of these genera may be sensitive to the fatty acid content of the diet. Human pregnancy has previously been reported to reduce the individual (alpha) diversity of the gut microbiota in humans (21) and rodents (15).…”

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma

“…Epidemiological studies have shown an association between NASH and HCC with an increased consumption of dietary fat, particularly saturated fats [19]. Saturated fatty acids (FAs) also stimulate release of the gastrointestinal (GI) peptide cholecystokinin (CCK), with a sharp cutoff in FA chain length [20,21].…”