Frutose role in steatohepatitis and its influence in colorectal cancer liver metastasis

A fat and sugar enriched diet can shape the stroma of the liver contributing to the pathogenesis of fatty and inflammatory hepatic chronic diseases such as non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) or even to hepatocellular carcinoma (HCC). In addition, the hepatic stroma plays an important role in metastatic growth, particularly from colorectal carcinoma (CRC). Each stromal component contribution to the development of hepatic metastasis has been described, examining how phenotypical changes induced by environmental stimuli such as alcohol abuse, high-fat diet or obesity are pivotal on it. Nevertheless, the specific role of fructose enriched diet, remains unknown. Since fructose consumption keeps increasing all over the world is crucial to study its potential effects in health. Herein, we assess how the actual increase in fructose consumption can affect the development of CRC hepatic metastasis through its effect on NASH. To do so, we have tested changes fructose-induced in the major cellular contributors to hepatic environment modulation during NASH development (macrophages and hepatic stellate cells, HSC) and in CRC cells. We also evaluated the overall survival of mice treated with a high-fat high-fructose diet in front of a control group (high-fat diet) and probed high-fructose ingest effect after an inflammatory pulse in the liver. In vitro tests identified fructose as a relevant factor for hepatic stromal cells activity but didn’t appear to be relevant for CRC cells phenotype, elucidating that any change in hepatic metastasis incidence would be induced by stroma modification rather than because of metastatic cell affection. On the other hand, the data collected from in vivo assays was not conclusive. The combination of high-fructose dose plus hepatic inflammatory pulse revealed to increase hepatic inflammatory response. Nevertheless, the chronic model of CRC metastatic high-fructose exposed mice overall survival was higher than the control.Peer reviewe