Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a; Fabp5; Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis

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Hepatocellular carcinoma (HCC) accounts for 85% of primary liver cancer, the third most common cause of cancer-related deaths worldwide. Its incidence has been increasing in both men and women. In Western countries, high-calorie diets, mainly rich in carbohydrates such as fructose, represent a significant concern due to their repercussions on the population’s health. A high-fructose diet is related to the development of Metabolic-Associated Fatty Liver Disease (MAFLD), formerly named Non-Alcoholic Fatty Liver Disease (NAFLD), and the progression of HCC as it potentiates the lipogenic pathway and the accumulation of lipids. However, fructose metabolism seems to be different between the stages of the disease, carrying out a metabolic reprogramming to favor the proliferation, inflammation, and metastatic properties of cancer cells in HCC. This review focuses on a better understanding of fructose metabolism in both scenarios: MAFLD and HCC.