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Título: | Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC |
Autor: | Ribas, Vicent CSIC ORCID; Conde de la Rosa, Laura CSIC ORCID ; Robles, David CSIC; Nuñez, Susana CSIC; Segalés, Paula CSIC; Insausti, Naroa CSIC ORCID; Solsona-Vilarrasa, Estel CSIC ORCID; Fernández-Checa, José C. CSIC ORCID; García-Ruiz, Carmen CSIC ORCID | Palabras clave: | Cholesterol Hepatocellular carcinoma Steatosis NASH |
Fecha de publicación: | 13-ago-2021 | Editor: | Molecular Diversity Preservation International | Citación: | Cancers 13(16): 4091 (2021) | Resumen: | The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation of different lipid species, and cholesterol has emerged as an important player in NASH development, which has been shown to promote NASH-driven HCC. However, recent findings indicated a tumor suppressor role of cholesterol in liver carcinogenesis and HCC development. Thus, we examined the contribution of hepatic steatosis with or without cholesterol accumulation induced by dietary or genetic approaches in liver tumorigenesis and whether the role of cholesterol in NASH-driven HCC is species-dependent. While diethylnitrosamine (DEN) treatment to rats or mice fed a choline-deficient diet decreased the hepatic steatosis, feeding an atherogenic diet enriched in cholesterol potentiated the liver tumor markers. Similar effects were observed in DEN-treated transgenic SREBP-2 mice but not wild-type (WT) mice fed a regular chow diet. Remarkably, long-term feeding of a high-fat high-cholesterol diet (HFHC) but not a high-fat diet (HFD) to WT mice caused severe NASH with spontaneous progression to HCC. A similar outcome was observed in MUP-uPA transgenic mice fed a HFHC diet, which resulted in increased liver tumors and expression of the genes involved in the immune checkpoints. Ezetimibe treatment ameliorated chronic liver disease and, more importantly, tumor multiplicity in HFHC-fed MUP-uPA mice or DEN-treated WT mice. Thus, these results revealed a differential role of steatosis and cholesterol in NASH-driven HCC and indicated that the tumor-promoter role of cholesterol is species-independent and associated with impaired immunosurveillance | Versión del editor: | http://dx.doi.org/10.3390/cancers13164091 | URI: | http://hdl.handle.net/10261/260210 | DOI: | 10.3390/cancers13164091 | Identificadores: | doi: 10.3390/cancers13164091 e-issn: 2072-6694 |
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