Zheng, K. (Kang)

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    Activation of the unfolded protein response (UPR) is associated with cholangiocellular injury, fibrosis and carcinogenesis in an experimental model of fibropolycystic liver disease
    (2022) Latasa, M.U. (María Ujué); Bañares, R. (Rafael); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Nevzorova, Y. (Yulia); Peligros, M.I. (María Isabel); Nelson, L.J. (Leonard J.); Avila, M.A. (Matías Antonio); Davis, R.J. (Roger J.); Tortajada, A. (Agustín); Wu, H. (Hanghang); Vidal, A. (August); Rodriguez-Perales, S. (Sandra); Ye, H. (Hui); Reissing, J. (Johanna); Mohamed, M.R. (Mohamed Ramadan); Iraburu-Elizalde, M. (María); Lujambio, A. (Amaya); Martínez-Naves, E. (Eduardo); Trautwein, C. (Christian); Villanueva, A. (Alberto); Vaquero, J. (Javier); Colyn, L. (Leticia); Torres-Ruiz, R. (Raúl); Zheng, K. (Kang); Bruns, T. (Tony); Cubero, F.J. (Francisco Javier); Chen, C. (Chaobo)
    Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development.
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    An experimental DUAL model of advanced liver damage
    (2021) Bañares, R. (Rafael); Asensio, I. (Iris); Guo, F. (Feifei); Raquel; Singh, Y. (Youvika); Nevzorova, Y. (Yulia); Nakaya, H.I. (Helder I.); Ampuero, J. (Javier); Gómez, M. (Manuel); Peligros, M.I. (María Isabel); Avila, M.A. (Matías Antonio); Estévez-Vázquez, O. (Olga); López-Alcántara, N. (Nuria); Juárez, I. (Ignacio); Reissing, J. (Johanna); Liedtke, C. (Christian); Morán, L. (Laura); Santamaría, E. (Eva); Lamas-Paz, A. (Arantxa); Trautwein, C. (Christian); Vaquero, J. (Javier); Haas, U. (Ute); Martín-Villa, J.M. (José Manuel); Woitok, M.M. (Marius Maximilian); Bataller, R. (Ramón); Mazariegos, M.S. (Marina S.); Gómez-del-Moral, M. (Manuel); Zheng, K. (Kang); Bruns, T. (Tony); Cubero, F.J. (Francisco Javier); Argemí, J. (Josepmaria); Chen, C. (Chaobo)
    Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.