Guo, FeifeiEstevez Vázquez, OlgaBenedé Ubieto, RaquelMaya Mile, DouglasZheng, KangGallego Durán, RocíoRojas Ávalos, ÁngelaAmpuero, JavierRomero Gómez, ManuelPhilip, KayeEgbuniwe, Isioma U.Chen, ChaoboSimon, JorgeDelgado, Teresa C.Martínez Chantar, Maria L.Sun, JieReissing, JohannaBruns, TonyLamas Paz, ArantzaWoitok, Marius MaximilianRegueiro, José R.Liedtke, ChristianTrautwein, ChristianBañares Cañizares, RafaelCubero Palero, Francisco JavierBenede Ubieto, RaquelGómez Del Moral Martín-Consuegra, Manuel MaríaVaquero Martín, Francisco JavierNevzorova, Yulia2023-06-222023-06-222021-12-312072-669410.3390/cancers14010192https://hdl.handle.net/20.500.14352/71932Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.engAtribución 3.0 Españajournal articlehttps://doi.org/10.3390/cancers14010192open access616-006.04:616.36metabolic-associated fatty liver disease (MAFLD)c-myconcogenetumorigenesismetforminGastroenterología y hepatologíaOncología3205.03 Gastroenterología3201.01 Oncología