Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

Am J Physiol Endocrinol Metab. 2020 Sep 14. doi: 10.1152/ajpendo.00321.2020. Online ahead of print.


Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can progress into non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Western diets, high in fats, sugars and cholesterol are linked to NAFLD development. Murine models are often used to study NAFLD; however, there remains debate on which diet-induced model best mimics both human disease progression and pathogenesis. In this study, we performed a side-by-side comparison of two popular diet models of murine NAFLD/NASH and associated HCC: a high fat diet supplemented with 30% fructose water (HFHF) and a western diet high in cholesterol (WDHC), comparing them to a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, while WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumour burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. This study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC are reliable methods to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.

Keywords: HCC; NAFLD; NASH; diet; mouse models.