The impact of Cyclin E1 in alcohol-induced organ disease and carcinogenesis within the Gut-liver axis
Final Report Abstract
During funding period, I have focused my research on ALD. The set of important goals was successfully achieved in this project: ü We performed detailed characterization of Cyclin E1 knockout mice in the acute and chronic models of ALD and identified the effector cells for the Cyclin E1-driven effects. For the first time we showed that the deletion of cyclin E1 in hepatocytes changes the expression of genes involved in alcohol metabolism and results in the pronounced susceptibility to ethanol-derived liver injury. We showed that mice develop alterations in the gut-liver axis in response to experimental acute alcohol intoxication. Overall, alterations in the intestinal epithelial barrier associated to increased permeability a thinner mucous protective layer and alterations in gut microbiota. We provided evidence that the extrinsic, Caspase-8-dependent apoptosis pathway is dispensable for the initiation and progression of ALD as hepatocytes are capable to switch to intrinsic cell death upon Caspase-8 deficiency. Therefore, only a combined approach using a pan-caspase inhibitor completely blocking caspase activity in hepatocytes might be an optimal approach for the treatment of ALD. We developed and published an innovative experimental DUAL murine model which resembles the compound effects of alcohol and WD. This preclinical model might be wellconsidered as a useful experimental model to study the dangerous combination of ALD plus NAFLD in human, and therefore be further used for the development of so much needed therapeutic options. We highlighted the role of E-type cyclins in the experimental model of liver cancer. At the moment, we applying the physiological DUAL diet to cyclin E1 conditional and constitutive mice. In addition, we discussed and highlighted the important topics in the field of hepatology in a few reviews: 1. Animal models and experimental procedures in hepatology. 2. Chronic liver diseases and carcinogenesis. Alltogeter, our work will significantly advance our fundamental understanding of ALD and associated gut-liver interaction and alcohol-induced cancer. Despite this proposal does not have immediate translational application in the clinical setting, the results and knowledge generated during the development of this project have high potential to impact clinical practice and hold the promise to improve diagnostic and patient care, open new avenues for the treatment of patients with ALD in the future.
Publications
- Inhibition of Caspase-8 does not protect from alcohol-induced liver apoptosis but alleviates alcoholic hepatic steatosis in mice. Cell Death Dis 8, e3152 (2017)
Hao, F., Cubero, F.J., Lijun, L., Ramadori, P., Streetz, K.L., Haas, U., Lambertz, D., Gassler, N., Hoss, M., Reissing, J., Zimmermann, H.W., Trautwein, C., Liedtke, C., Nevzorova, Y.A.
(See online at https://doi.org/10.1038/cddis.2017.532) - Cyclin E1 and cyclindependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma. Proc Natl Acad Sci U S
A 2018
Sonntag, R., Giebeler, N., Nevzorova, Y.A., Bangen, JM., Fahrenkamp, D., Lambertz, D., Haas, U., Gassler, N., Cubero, F.J., Müller-Newen, G., Abdallah, A.T., Weiskirchen, R., Ticconi, F., Costa, I.G., Barbacid, M., Trautwein, C., Liedtke, C.
(See online at https://doi.org/10.1073/pnas.1807155115) - p38gamma is essential for cell cycle progression and liver tumorigenesis. Nature 2019;568:557-560
Tomas-Loba, A., Manieri, E., Gonzalez-Teran, B., Mora, A., Leiva-Vega, L., Santamans, A. M., Romero-Becerra, R., Rodriguez, E., Pintor-Chocano, A., Feixas, F., Lopez, J. A., Caballero, B., Trakala, M., Blanco, O., Torres, J. L., Hernandez-Cosido, L., Montalvo-Romeral, V., Matesanz, N., Roche-Molina, M., Bernal, J. A., Mischo, H., Leon, M., Caballero, A., Miranda-Saavedra, D., Ruiz- Cabello, J., Nevzorova, Y. A., Cubero, F. J., Bravo, J., Vazquez, J., Malumbres, M., Marcos, M., Osuna, S. and Sabio, G.
(See online at https://doi.org/10.1038/s41586-019-1112-8) - Intestinal epithelial cell-derived extracellular vesicles (EVs) modulate hepatic injury via the gut-liver axis during acute alcohol injury. Frontiers in Pharmacology 2020;11:1738
Lamas-Paz, A., Morán, L., Peng, J., Salinas, B., Lopez-Alcántara, N., Sydor, S., Vilchez- Vargas, R., Asensio, I., Hao, F., Zheng, K., Martín-Adrados, B., Moreno, L., Cogolludo, A., Gómez del Moral, M., Bechmann, L., Martinez-Naves, E., Vaquero, J., Bañares, R., Nevzorova, Y.A. , Cubero, F. J
(See online at https://doi.org/10.3389/fphar.2020.603771) - Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma. Hepatol Commun 2020; 4:834-851
Cubero, F.J., Mohamed, M.R., Woitok, M.M., Zhao, G., Hatting, M., Nevzorova, Y.A., Chen, C., et al.
(See online at https://doi.org/10.1002/hep4.1495) - Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti- Fibrotic Effects in Hepatic Stellate Cells In Vitro. Int J Mol Sci 2020;21
Hubbers, A., Hennings, J., Lambertz, D., Haas U, Trautwein, C., Nevzorova, Y.A., Sonntag, R., et al.
(See online at https://doi.org/10.3390/ijms21093267) - A novel experimental DUAL model of advanced liver damage
. Hepatology Comunication, 2021
Benedé-Ubieto R., Estévez-Vázquez O., Guo F., Chen, C, Singh, Y., Nakaya, H., Gómez del Moral, M., Lamas-Paz, A., Morán, L., López-Alcántara, N., Reissing, J., Bruns, T., Avila, M., Santamaría, E., Mazariegos, M.S., Woitok, M.M, Haas, U., Zheng, K., Juárez, I., Martín- Villa J.M., Asensio, I., Vaquero, J., Peligros, M.I., Argemi, J., Bataller, R., Ampuero, J., Gómez M.R., Trautwein C., Liedtke C., Bañares, R., Cubero, F. J., Nevzorova Y.A.
(See online at https://doi.org/10.1002/hep4.1698)
