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47 results on '"Aurrekoetxea, Igor"'

3. FRI-472-YI Mitochondrial metabolism is disrupted by ciprofloxacin preventing cholangiocarcinoma cell proliferation

Author

de Gauna, Mikel Ruiz, primary, Alfaro-Jiménez, Kendall, additional, Nieva-Zuluaga, Ane, additional, Apodaka-Biguri, Maider, additional, Markaide, Enara, additional, Izquierdo-Sánchez, Laura, additional, Rae, Colin, additional, González-Romero, Francisco, additional, Gomez-Jauregui, Paul, additional, Sainz-Ramírez, Natalia, additional, Santos, Beatriz Gómez, additional, Buque, Xabier, additional, Aurrekoetxea, Igor, additional, Delgado, Igotz, additional, Fernández-Puertas, Idoia, additional, Iglesias, Ainhoa, additional, Rourke, Colm O., additional, Rodrigues, Pedro Miguel, additional, Andersen, Jesper, additional, Calvisi, Diego, additional, Morton, Jennifer, additional, Braconi, Chiara, additional, Zubiaga, Ana, additional, Banales, Jesus Maria, additional, and Aspichueta, Patricia, additional

Published
2024
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4. THU-210 Dysfunctional activation of the DNA damage response is associated with MASLD progression through an E2F2-dependent mechanism

Author

Santos, Beatriz Gómez, primary, Fernández-Puertas, Idoia, additional, Gomez-Jauregui, Paul, additional, Sainz-Ramírez, Natalia, additional, Alfaro-Jiménez, Kendall, additional, Castillero, Estibaliz, additional, Nieva-Zuluaga, Ane, additional, Apodaka-Biguri, Maider, additional, Aurrekoetxea, Igor, additional, Delgado, Igotz, additional, Lopategi, Aritz, additional, Iglesias, Ainhoa, additional, González, Lorena Mosteiro, additional, Olartekoetxea, Gaizka Errazti, additional, Gaztambide, Sonia, additional, González, Luis A. Castaño, additional, Bujanda, Luis, additional, Banales, Jesus Maria, additional, Buque, Xabier, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2024
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5. FRI-343-YI APAP induced liver damage is prevented by activation of PPARgamma and PPAR-alpha

Author

Gomez-Jauregui, Paul, primary, Gonzalez-Romero, Francisco, additional, Santos, Beatriz Gómez, additional, Apodaka-Biguri, Maider, additional, Buque, Xabier, additional, Crespo, Maria, additional, Mora, Alfonso, additional, Mesquita, Mariana, additional, Aurrekoetxea, Igor, additional, Delgado, Igotz, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Fernández-Puertas, Idoia, additional, Sainz-Ramírez, Natalia, additional, Alfaro-Jiménez, Kendall, additional, Irizar, María Esther, additional, Iglesias, Ainhoa, additional, Cubero, Francisco Javier, additional, Sabio, Guadalupe, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2024
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6. OS-101-YI Remodelling of hepatocyte cholesterol metabolism mediates colorectal liver metastasis

Author

Nieva-Zuluaga, Ane, primary, Arteta, Beatriz, additional, de Gauna, Mikel Ruiz, additional, Apodaka-Biguri, Maider, additional, Fernández-Puertas, Idoia, additional, González-Romero, Francisco, additional, Gomez-Jauregui, Paul, additional, Sainz-Ramírez, Natalia, additional, Alfaro-Jiménez, Kendall, additional, Santos, Beatriz Gómez, additional, Delgado, Igotz, additional, Valdivieso, Andres, additional, Bustamante, Javier, additional, Bujanda, Luis, additional, Banales, Jesus Maria, additional, Giannou, Anastasios, additional, Huber, Samuel, additional, Aurrekoetxea, Igor, additional, Buque, Xabier, additional, and Aspichueta, Patricia, additional

Published
2024
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7. TOP-229-YI The E2F2 target glycerophosphodiester phosphodiesterase domain containing 3 is involved in MASLD progression to HCC and related dyslipidemias

Author

Apodaka-Biguri, Maider, primary, Muñoz-Llanes, Nerea, additional, Gonzalez-Romero, Francisco, additional, Aurrekoetxea, Igor, additional, Santos, Beatriz Gómez, additional, Delgado, Igotz, additional, Buque, Xabier, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Fernández-Puertas, Idoia, additional, Gomez-Jauregui, Paul, additional, Sainz-Ramírez, Natalia, additional, Alfaro-Jiménez, Kendall, additional, Castillero, Estibaliz, additional, Congregado, Daniela Mestre, additional, Woodhoo, Ashwin, additional, Varela-Rey, Marta, additional, Lujambio, Amaia, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2024
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8. Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis

Author

Sáenz de Urturi, Diego, Buqué, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C., Prieto-Fernández, Endika, Olaizola, Paula, Gómez-Santos, Beatriz, Apodaka-Biguri, Maider, González-Romero, Francisco, Nieva-Zuluaga, Ane, Ruiz de Gauna, Mikel, Goikoetxea-Usandizaga, Naroa, García-Rodríguez, Juan Luis, Gutierrez de Juan, Virginia, Aurrekoetxea, Igor, Montalvo-Romeral, Valle, Novoa, Eva M., Martín-Guerrero, Idoia, Varela-Rey, Marta, Bhanot, Sanjay, Lee, Richard, Banales, Jesus M., Syn, Wing-Kin, Sabio, Guadalupe, Martínez-Chantar, María L., Nogueiras, Rubén, and Aspichueta, Patricia

Published
2022
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9. Role of Aramchol in steatohepatitis and fibrosis in mice.

Author

Iruarrizaga-Lejarreta, Marta, Varela-Rey, Marta, Fernández-Ramos, David, Martínez-Arranz, Ibon, Delgado, Teresa C, Simon, Jorge, Juan, Virginia Gutiérrez-de, delaCruz-Villar, Laura, Azkargorta, Mikel, Lavin, José L, Mayo, Rebeca, Van Liempd, Sebastiaan M, Aurrekoetxea, Igor, Buqué, Xabier, Cave, Donatella Delle, Peña, Arantza, Rodríguez-Cuesta, Juan, Aransay, Ana M, Elortza, Felix, Falcón-Pérez, Juan M, Aspichueta, Patricia, Hayardeny, Liat, Noureddin, Mazen, Sanyal, Arun J, Alonso, Cristina, Anguita, Juan, Martínez-Chantar, María Luz, Lu, Shelly C, and Mato, José M

Subjects
1-carbon metabolism, Lipid metabolism, Mouse model, S-adenosylmethionine
Abstract

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) which sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits including oxidative stress, mitochondrial dysfunction, inflammation and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Aramchol (arachidyl-amido cholanoic acid) is presently in a phase IIb NASH study. The aim of this study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine- and choline-deficient (MCD) diet model of NASH. We collected liver and serum from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks, which developed steatohepatitis and fibrosis, as well as mice receiving a control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride biosynthesis whose loss enhances fatty acid β-oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of serum metabolomic pattern between 0.1MCD fed mice and NAFLD patients showed a substantial overlap. Conclusions:Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of NAFLD patients, which supports the potential use of Aramchol in NASH treatment.

Published
2017

10. Deregulated neddylation in liver fibrosis

Author

Zubiete‐Franco, Imanol, Fernández‐Tussy, Pablo, Barbier‐Torres, Lucía, Simon, Jorge, Fernández‐Ramos, David, Lopitz‐Otsoa, Fernando, Juan, Virginia Gutiérrez‐de, de Davalillo, Sergio López, Duce, Antonio Martín, Iruzubieta, Paula, Taibo, Daniel, Crespo, Javier, Caballeria, Juan, Villa, Erica, Aurrekoetxea, Igor, Aspichueta, Patricia, Varela‐Rey, Marta, Lu, Shelly C, Mato, José M, Beraza, Naiara, Delgado, Teresa C, and Martínez‐Chantar, María L

Subjects
Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Aetiology, Oral and gastrointestinal, Good Health and Well Being, Aging, Analysis of Variance, Animals, Apoptosis, Biopsy, Needle, Cell Proliferation, Cell Survival, Cells, Cultured, Chemokine CCL4, Chemokines, Cyclopentanes, Disease Models, Animal, Hepatic Stellate Cells, Humans, Immunohistochemistry, Liver Cirrhosis, Male, Mice, Mice, Inbred C57BL, NEDD8 Protein, Pyrimidines, Random Allocation, Signal Transduction, Ubiquitins, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances.ConclusionNeddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).

Published
2017

11. The E2F2-miR34a-5p axis is involved in the biliary metabolism dysregulation in NASH

Author

Apodaka-Biguri, Maider, primary, Gonzalez-Romero, Francisco, additional, Simão, André L., additional, Congregado, Daniela Mestre, additional, Aurrekoetxea, Igor, additional, Santos, Beatriz Gómez, additional, Delgado, Igotz, additional, Buque, Xabier, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Fernández-Puertas, Idoia, additional, Iglesias, Ainhoa, additional, Aransay, Ana María, additional, Lozano, Juanjo, additional, Martín, Cesar Augusto, additional, Bernales, Irantzu, additional, Rodrigues, Pedro Miguel, additional, Banales, Jesus Maria, additional, Zubiaga, Ana, additional, Castro, Rui E., additional, and Aspichueta, Patricia, additional

Published
2023
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12. Targeting the E2F/MCM axis in cholangiocarcinoma halts disease progression in experimental models by rewiring lipid metabolism

Author

de Gauna, Mikel Ruiz, primary, Nieva-Zuluaga, Ane, additional, Apodaka-Biguri, Maider, additional, González-Romero, Francisco, additional, Muñoz-Llanes, Nerea, additional, Gomez-Jauregui, Paul, additional, Sainz-Ramírez, Natalia, additional, Alfaro-Jiménez, Kendall, additional, Santos, Beatriz Gómez, additional, Buque, Xabier, additional, Aurrekoetxea, Igor, additional, Delgado, Igotz, additional, Fernández-Puertas, Idoia, additional, Iglesias, Ainhoa, additional, Rodrigues, Pedro Miguel, additional, Calvisi, Diego, additional, Zubiaga, Ana, additional, Banales, Jesus Maria, additional, and Aspichueta, Patricia, additional

Published
2023
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13. E2F2 deficiency protects from acetaminophen-induced hepatotoxicity while E2F1 is required to prevent the devastating effects

Author

Buque, Xabier, primary, Gonzalez-Romero, Francisco, additional, Apodaka-Biguri, Maider, additional, Crespo, Maria, additional, Mesquita, Mariana, additional, Aurrekoetxea, Igor, additional, Santos, Beatriz Gómez, additional, Delgado, Igotz, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Fernández-Puertas, Idoia, additional, Gomez-Jauregui, Paul, additional, Muñoz-Llanes, Nerea, additional, Sainz-Ramírez, Natalia, additional, Iglesias, Ainhoa, additional, Cubero, Francisco Javier, additional, Sabio, Guadalupe, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2023
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14. E2F2-promoted DNA damage in NASH worsens the metabolic scenario

Author

Santos, Beatriz Gómez, primary, Fernández-Puertas, Idoia, additional, Gomez-Jauregui, Paul, additional, Muñoz-Llanes, Nerea, additional, Sainz-Ramírez, Natalia, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Apodaka-Biguri, Maider, additional, González-Romero, Francisco, additional, Delgado, Igotz, additional, Aurrekoetxea, Igor, additional, González, Lorena Mosteiro, additional, Olartekoetxea, Gaizka Errazti, additional, Gaztambide, Sonia, additional, Castaño González, Luis A, additional, Bujanda, Luis, additional, Banales, Jesus Maria, additional, Buque, Xabier, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2023
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15. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Author

Martínez-Sánchez, Noelia, Seoane-Collazo, Patricia, Contreras, Cristina, Varela, Luis, Villarroya, Joan, Rial-Pensado, Eva, Buqué, Xabier, Aurrekoetxea, Igor, Delgado, Teresa C., Vázquez-Martínez, Rafael, González-García, Ismael, Roa, Juan, Whittle, Andrew J., Gomez-Santos, Beatriz, Velagapudi, Vidya, Tung, Y.C. Loraine, Morgan, Donald A., Voshol, Peter J., Martínez de Morentin, Pablo B., López-González, Tania, Liñares-Pose, Laura, Gonzalez, Francisco, Chatterjee, Krishna, Sobrino, Tomás, Medina-Gómez, Gema, Davis, Roger J., Casals, Núria, Orešič, Matej, Coll, Anthony P., Vidal-Puig, Antonio, Mittag, Jens, Tena-Sempere, Manuel, Malagón, María M., Diéguez, Carlos, Martínez-Chantar, María Luz, Aspichueta, Patricia, Rahmouni, Kamal, Nogueiras, Rubén, Sabio, Guadalupe, Villarroya, Francesc, and López, Miguel

Published
2017
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16. Data from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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17. Supplementary Information from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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18. Supplementary Table 1 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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19. Supplementary Data from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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20. Supplementary Table 2 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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21. Supplementary Figures from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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22. Supplementary Table 3 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary

Published
2023
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23. S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease

Author

Martínez-Uña, Maite, Varela-Rey, Marta, Mestre, Daniela, Fernández-Ares, Larraitz, Fresnedo, Olatz, Fernandez-Ramos, David, Juan, Virginia Gutiérrez-de, Martin-Guerrero, Idoia, García-Orad, Africa, Luka, Zigmund, Wagner, Conrad, Lu, Shelly C., García-Monzón, Carmelo, Finnell, Richard H., Aurrekoetxea, Igor, Buqué, Xabier, Martínez-Chantar, M. Luz, Mato, José M., and Aspichueta, Patricia

Published
2015
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25. The uptake of extracellular lipids promotes cholangiocarcinoma progression

Author

de Gauna, Mikel Ruiz, primary, Biancaniello, Francesca, additional, González-Romero, Francisco, additional, Rodrigues, Pedro Miguel, additional, Lapitz, Ainhoa, additional, Santos, Beatriz Gómez, additional, Olaizola, Paula, additional, Di Matteo, Sabina, additional, Aurrekoetxea, Igor, additional, Labiano, Ibone, additional, Nieva-Zuluaga, Ane, additional, Benito-Vicente, Asier, additional, Perugorria, María Jesús, additional, Apodaka-Biguri, Maider, additional, Paiva, Nuno, additional, de Urturi, Diego Saenz, additional, Buque, Xabier, additional, Delgado, Igotz, additional, Martín, Cesar Augusto, additional, Azkargorta, Mikel, additional, Elortza, Felix, additional, Calvisi, Diego, additional, Andersen, Jesper, additional, Alvaro, Domenico, additional, Cardinale, Vincenzo, additional, Bujanda, Luis, additional, Banales, Jesus Maria, additional, and Aspichueta, Patricia, additional

Published
2022
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26. miR34a-5p is a target of E2F2 transcription factor in MAFLD-related HCC

Author

Apodaka-Biguri, Maider, primary, Gonzalez-Romero, Francisco, additional, Congregado, Daniela Mestre, additional, Aurrekoetxea, Igor, additional, Santos, Beatriz Gómez, additional, Delgado, Igotz, additional, Buque, Xabier, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Fernámdez-Puertas, Idoia, additional, Iglesias, Ainhoa, additional, Aransay, Ana María, additional, Lozano, Juanjo, additional, Martín, Cesar Augusto, additional, Bernales, Irantzu, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2022
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27. Methionine adenosyltransferase 1a antisense oligonucleotides induce the fibroblast growth factor 21-driven recovery from obesity and associated hepatoesteatosis

Author

Buque, Xabier, primary, de Urturi, Diego Saenz, additional, Porteiro, Begoña, additional, Folgueira, Cintia, additional, Mora, Alfonso, additional, Delgado, Teresa Cardoso, additional, Prieto-Fernández, Endika, additional, Olaizola, Paula, additional, Santos, Beatriz Gómez, additional, Apodaka-Biguri, Maider, additional, Gonzalez-Romero, Francisco, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Goikoetxea, Naroa, additional, García Rodríguez, Juan Luis, additional, de Juan, Virginia Gutiérrez, additional, Aurrekoetxea, Igor, additional, Montalvo-Romeral, Valle, additional, Novoa, Eva, additional, Martin-Guerrero, Idoia, additional, Varela-Rey, Marta, additional, Bhanot, Sanjay, additional, Lee, Richard, additional, Banales, Jesus Maria, additional, Syn, Wing-Kin, additional, Sabio, Guadalupe, additional, Martínez-Chantar, María Luz, additional, Nogueiras, Ruben, additional, and Aspichueta, Patricia, additional

Published
2022
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28. The DNA damage response is involved in the metabolic dysregulation of MAFLD patients via inefficient fatty acid oxidation

Author

Santos, Beatriz Gómez, primary, Fernámdez-Puertas, Idoia, additional, Nieva-Zuluaga, Ane, additional, de Gauna, Mikel Ruiz, additional, Apodaka-Biguri, Maider, additional, González-Romero, Francisco, additional, de Urturi, Diego Saenz, additional, Delgado, Igotz, additional, Aurrekoetxea, Igor, additional, González, Lorena Mosteiro, additional, Olartekoetxea, Gaizka Errazti, additional, Gaztambide, Sonia, additional, Castaño González, Luis A, additional, Bujanda, Luis, additional, Banales, Jesus Maria, additional, Zubiaga, Ana, additional, Buque, Xabier, additional, and Aspichueta, Patricia, additional

Published
2022
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29. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Universidad del País Vasco, Instituto de Salud Carlos III, Diputación Foral de Gipuzkoa, Eusko Jaurlaritza, Fundación Vasca de Innovación e Investigación Sanitarias, Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, AMMF - The Cholangiocarcinoma Charity, Ministerio de Economía y Competitividad (España), Ruiz de Gauna, Mikel, Biancaniello, Francesca, González-Romero, Francisco, Rodrigues, Pedro M., Lapitz, Ainhoa, Gómez-Santos, Beatriz, Olaizola, Paula, Di Matteo, Sabina, Aurrekoetxea, Igor, Labiano, Ibone, Nieva, Ane, Benito-Vicente, Asier, Perrugorria, María J., Apodaka, Maider, Paiva, Nuno A., Sáenz de Urturi, Diego, Buqué, Xabier, Delgado, Igotz, Martín, César, Azkargorta, Mikel, Elortza, Félix, Calvisi, Diego F., Andersen, Jesper B., Álvaro, Domenico, Cardinale, Vincenzo, Bujanda, Luis, Banales, Jesús M., Aspichueta, Patricia, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Universidad del País Vasco, Instituto de Salud Carlos III, Diputación Foral de Gipuzkoa, Eusko Jaurlaritza, Fundación Vasca de Innovación e Investigación Sanitarias, Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, AMMF - The Cholangiocarcinoma Charity, Ministerio de Economía y Competitividad (España), Ruiz de Gauna, Mikel, Biancaniello, Francesca, González-Romero, Francisco, Rodrigues, Pedro M., Lapitz, Ainhoa, Gómez-Santos, Beatriz, Olaizola, Paula, Di Matteo, Sabina, Aurrekoetxea, Igor, Labiano, Ibone, Nieva, Ane, Benito-Vicente, Asier, Perrugorria, María J., Apodaka, Maider, Paiva, Nuno A., Sáenz de Urturi, Diego, Buqué, Xabier, Delgado, Igotz, Martín, César, Azkargorta, Mikel, Elortza, Félix, Calvisi, Diego F., Andersen, Jesper B., Álvaro, Domenico, Cardinale, Vincenzo, Bujanda, Luis, Banales, Jesús M., and Aspichueta, Patricia

Abstract

[Background and Aims] Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation., [Approach and Results] The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA., [Conclusions] Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.

Published
2022

30. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Author

Ruiz de Gauna, Mikel, Biancaniello, Francesca, González-Romero, Francisco, Rodrigues, Pedro M., Lapitz, Ainhoa, Gómez-Santos, Beatriz, Olaizola, Paula, Di Matteo, Sabina, Aurrekoetxea, Igor, Labiano, Ibone, Nieva-Zuluaga, Ane, Benito-Vicente, Asier, Perugorria, María J., Apodaka-Biguri, Maider, Paiva, Nuno A., Sáenz de Urturi, Diego, Buqué, Xabier, Delgado, Igotz, Martín, César, Azkargorta, Mikel, Elortza, Felix, Calvisi, Diego F., Andersen, Jesper B., Alvaro, Domenico, Cardinale, Vincenzo, Bujanda, Luis, Banales, Jesús M, Aspichueta, Patricia, Ruiz de Gauna, Mikel, Biancaniello, Francesca, González-Romero, Francisco, Rodrigues, Pedro M., Lapitz, Ainhoa, Gómez-Santos, Beatriz, Olaizola, Paula, Di Matteo, Sabina, Aurrekoetxea, Igor, Labiano, Ibone, Nieva-Zuluaga, Ane, Benito-Vicente, Asier, Perugorria, María J., Apodaka-Biguri, Maider, Paiva, Nuno A., Sáenz de Urturi, Diego, Buqué, Xabier, Delgado, Igotz, Martín, César, Azkargorta, Mikel, Elortza, Felix, Calvisi, Diego F., Andersen, Jesper B., Alvaro, Domenico, Cardinale, Vincenzo, Bujanda, Luis, Banales, Jesús M, and Aspichueta, Patricia

Abstract

Background and Aims: Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation. Approach and Results: The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA. Conclusions: Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.

Published
2022

31. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Author

Ruiz de Gauna, Mikel, primary, Biancaniello, Francesca, additional, González‐Romero, Francisco, additional, Rodrigues, Pedro M., additional, Lapitz, Ainhoa, additional, Gómez‐Santos, Beatriz, additional, Olaizola, Paula, additional, Di Matteo, Sabina, additional, Aurrekoetxea, Igor, additional, Labiano, Ibone, additional, Nieva‐Zuluaga, Ane, additional, Benito‐Vicente, Asier, additional, Perugorria, María J., additional, Apodaka‐Biguri, Maider, additional, Paiva, Nuno A., additional, Sáenz de Urturi, Diego, additional, Buqué, Xabier, additional, Delgado, Igotz, additional, Martín, César, additional, Azkargorta, Mikel, additional, Elortza, Felix, additional, Calvisi, Diego F., additional, Andersen, Jesper B., additional, Alvaro, Domenico, additional, Cardinale, Vincenzo, additional, Bujanda, Luis, additional, Banales, Jesús M., additional, and Aspichueta, Patricia, additional

Published
2022
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32. E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment

Author

Gonzalez-Romero, Francisco, Mestre, Daniela, Aurrekoetxea, Igor, O'Rourke, Colm J., Andersen, Jesper B., Woodhoo, Ashwin, Tamayo-Caro, Miguel, Varela-Rey, Marta, Palomo-Irigoyen, Marta, Gomez-Santos, Beatriz, de Urturi, Diego Saenz, Nuñez-García, Maitane, García-Rodríguez, Juan L., Fernandez-Ares, Larraitz, Buque, Xabier, Iglesias-Ara, Ainhoa, Bernales, Irantzu, de Juan, Virginia Gutierrez, Delgado, Teresa C., Goikoetxea-Usandizaga, Naroa, Lee, Richard, Bhanot, Sanjay, Delgado, Igotz, Perugorria, Maria J., Errazti, Gaizka, Mosteiro, Lorena, Gaztambide, Sonia, de la Piscina, Idoia Martinez, Iruzubieta, Paula, Crespo, Javier, Banales, Jesus M., Martínez-Chantar, Maria L., Castaño, Luis, Zubiaga, Ana M., Aspichueta, Patricia, Gonzalez-Romero, Francisco, Mestre, Daniela, Aurrekoetxea, Igor, O'Rourke, Colm J., Andersen, Jesper B., Woodhoo, Ashwin, Tamayo-Caro, Miguel, Varela-Rey, Marta, Palomo-Irigoyen, Marta, Gomez-Santos, Beatriz, de Urturi, Diego Saenz, Nuñez-García, Maitane, García-Rodríguez, Juan L., Fernandez-Ares, Larraitz, Buque, Xabier, Iglesias-Ara, Ainhoa, Bernales, Irantzu, de Juan, Virginia Gutierrez, Delgado, Teresa C., Goikoetxea-Usandizaga, Naroa, Lee, Richard, Bhanot, Sanjay, Delgado, Igotz, Perugorria, Maria J., Errazti, Gaizka, Mosteiro, Lorena, Gaztambide, Sonia, de la Piscina, Idoia Martinez, Iruzubieta, Paula, Crespo, Javier, Banales, Jesus M., Martínez-Chantar, Maria L., Castaño, Luis, Zubiaga, Ana M., and Aspichueta, Patricia

Abstract

Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1-/- and E2f2-/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1-/- and E2f2-/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis.

Published
2021

33. E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment

Author

González-Romero, Francisco, primary, Mestre, Daniela, additional, Aurrekoetxea, Igor, additional, O'Rourke, Colm J., additional, Andersen, Jesper B., additional, Woodhoo, Ashwin, additional, Tamayo-Caro, Miguel, additional, Varela-Rey, Marta, additional, Palomo-Irigoyen, Marta, additional, Gómez-Santos, Beatriz, additional, de Urturi, Diego Sáenz, additional, Núñez-García, Maitane, additional, García-Rodríguez, Juan L., additional, Fernández-Ares, Larraitz, additional, Buqué, Xabier, additional, Iglesias-Ara, Ainhoa, additional, Bernales, Irantzu, additional, De Juan, Virginia Gutierrez, additional, Delgado, Teresa C., additional, Goikoetxea-Usandizaga, Naroa, additional, Lee, Richard, additional, Bhanot, Sanjay, additional, Delgado, Igotz, additional, Perugorria, Maria J., additional, Errazti, Gaizka, additional, Mosteiro, Lorena, additional, Gaztambide, Sonia, additional, Martinez de la Piscina, Idoia, additional, Iruzubieta, Paula, additional, Crespo, Javier, additional, Banales, Jesus M., additional, Martínez-Chantar, Maria L., additional, Castaño, Luis, additional, Zubiaga, Ana M., additional, and Aspichueta, Patricia, additional

Published
2021
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34. WED-408 - E2F2-promoted DNA damage in NASH worsens the metabolic scenario

Author

Santos, Beatriz Gómez, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Muñoz-Llanes, Nerea, Sainz-Ramírez, Natalia, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Apodaka-Biguri, Maider, González-Romero, Francisco, Delgado, Igotz, Aurrekoetxea, Igor, González, Lorena Mosteiro, Olartekoetxea, Gaizka Errazti, Gaztambide, Sonia, Castaño González, Luis A, Bujanda, Luis, Banales, Jesus Maria, Buque, Xabier, Zubiaga, Ana, and Aspichueta, Patricia

Published
2023
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35. WED-404 - The E2F2-miR34a-5p axis is involved in the biliary metabolism dysregulation in NASH

Author

Apodaka-Biguri, Maider, Gonzalez-Romero, Francisco, Simão, André L., Congregado, Daniela Mestre, Aurrekoetxea, Igor, Santos, Beatriz Gómez, Delgado, Igotz, Buque, Xabier, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Iglesias, Ainhoa, Aransay, Ana María, Lozano, Juanjo, Martín, Cesar Augusto, Bernales, Irantzu, Rodrigues, Pedro Miguel, Banales, Jesus Maria, Zubiaga, Ana, Castro, Rui E., and Aspichueta, Patricia

Published
2023
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36. SAT-215 - Targeting the E2F/MCM axis in cholangiocarcinoma halts disease progression in experimental models by rewiring lipid metabolism

Author

de Gauna, Mikel Ruiz, Nieva-Zuluaga, Ane, Apodaka-Biguri, Maider, González-Romero, Francisco, Muñoz-Llanes, Nerea, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Santos, Beatriz Gómez, Buque, Xabier, Aurrekoetxea, Igor, Delgado, Igotz, Fernández-Puertas, Idoia, Iglesias, Ainhoa, Rodrigues, Pedro Miguel, Calvisi, Diego, Zubiaga, Ana, Banales, Jesus Maria, and Aspichueta, Patricia

Published
2023
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37. FRI-395 - E2F2 deficiency protects from acetaminophen-induced hepatotoxicity while E2F1 is required to prevent the devastating effects

Author

Buque, Xabier, Gonzalez-Romero, Francisco, Apodaka-Biguri, Maider, Crespo, Maria, Mesquita, Mariana, Aurrekoetxea, Igor, Santos, Beatriz Gómez, Delgado, Igotz, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Muñoz-Llanes, Nerea, Sainz-Ramírez, Natalia, Iglesias, Ainhoa, Cubero, Francisco Javier, Sabio, Guadalupe, Zubiaga, Ana, and Aspichueta, Patricia

Published
2023
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38. Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Xunta de Galicia, European Foundation for the Study of Diabetes, Instituto de Salud Carlos III, Fundación Francisco Cobos, Gómez-Santos, Beatriz [0000-0001-6607-7973], Aspichueta, Patricia [0000-0002-3553-1755], Gómez-Santos, Beatriz, Sáenz de Urturi, Diego, Núñez-García, Maitane, González-Romero, Francisco, Buqué, Xabier, Aurrekoetxea, Igor, Gutiérrez de Juan, Virginia, González-Rellán, María J., García-Monzón, Carmelo, González-Rodríguez, Águeda, Mosteiro, Lorena, Errazti, Gaizka, Mifsut, Patricia, Gaztambide, Sonia, Castaño, Luis, Martín, César, Nogueiras, Rubén, Martínez-Chantar, María Luz, Syn, Wing-Kin, Aspichueta, Patricia, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Xunta de Galicia, European Foundation for the Study of Diabetes, Instituto de Salud Carlos III, Fundación Francisco Cobos, Gómez-Santos, Beatriz [0000-0001-6607-7973], Aspichueta, Patricia [0000-0002-3553-1755], Gómez-Santos, Beatriz, Sáenz de Urturi, Diego, Núñez-García, Maitane, González-Romero, Francisco, Buqué, Xabier, Aurrekoetxea, Igor, Gutiérrez de Juan, Virginia, González-Rellán, María J., García-Monzón, Carmelo, González-Rodríguez, Águeda, Mosteiro, Lorena, Errazti, Gaizka, Mifsut, Patricia, Gaztambide, Sonia, Castaño, Luis, Martín, César, Nogueiras, Rubén, Martínez-Chantar, María Luz, Syn, Wing-Kin, and Aspichueta, Patricia

Abstract

Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of age-related hepatosteatosis.

Published
2020

39. Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

Author

Gómez‐Santos, Beatriz, primary, Saenz de Urturi, Diego, additional, Nuñez‐García, Maitane, additional, Gonzalez‐Romero, Francisco, additional, Buque, Xabier, additional, Aurrekoetxea, Igor, additional, Gutiérrez de Juan, Virginia, additional, Gonzalez‐Rellan, Maria J., additional, García‐Monzón, Carmelo, additional, González‐Rodríguez, Águeda, additional, Mosteiro, Lorena, additional, Errazti, Gaizka, additional, Mifsut, Patricia, additional, Gaztambide, Sonia, additional, Castaño, Luis, additional, Martin, Cesar, additional, Nogueiras, Rubén, additional, Martinez‐Chantar, María L., additional, Syn, Wing‐Kin, additional, and Aspichueta, Patricia, additional

Published
2020
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40. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

Author

Gil-Pitarch, Clàudia, Serrano-Maciá, Marina, Simon, Jorge, Mosca, Laura, Conter, Carolina, Rejano-Gordillo, Claudia M., Zapata-Pavas, L. Estefanía, Peña-Sanfélix, Patricia, Azkargorta, Mikel, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Mercado-Gómez, Maria, Delgado, Teresa C., Porcelli, Marina, Aurrekoetxea, Igor, Sutherland, James D., Barrio, Rosa, Xirodimas, Dimitris, Aspichueta, Patricia, Elortza, Felix, Martínez-Cruz, Luis Alfonso, Nogueiras, Rubén, Iruzubieta, Paula, Crespo, Javier, Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raul J., Lucena, M. Isabel, Mayor, Ugo, Goikoetxea-Usandizaga, Naroa, González-Recio, Irene, and Martínez-Chantar, María L.

Abstract

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

Published
2024
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41. PS-008-E2F2 mediated repression of fatty acid B-oxidation is mitigated through CREB1 in progressive non-alcoholic fatty liver disease

Author

Gonzalez-Romero, Francisco, primary, Mestre, Daniela, additional, Aurrekoetxea, Igor, additional, Urturi, Diego Sáenz de, additional, Gomez-Santos, Beatriz, additional, Nuñez-García, Maitane, additional, Buqué, Xabier, additional, Delgado, Igotz, additional, Palomo-Irigoyen, Marta, additional, Tamayo-Caro, Miguel, additional, Woodhoo, Ashwin, additional, Varela-Rey, Marta, additional, Martínez-Chantar, María Luz, additional, Iglesias, Ainhoa, additional, Lee, Richard, additional, Bhanot, Sanjay, additional, Zubiaga, Ana, additional, and Aspichueta, Patricia, additional

Published
2019
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42. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Martinez-Sanchez, Noelia, Seoane-Collazo, Patricia, Contreras, Cristina, Varela, Luis, Villarroya, Joan, Rial-Pensado, Eva, Buque, Xabier, Aurrekoetxea, Igor, Delgado, Teresa C., Vazquez-Martinez, Rafael, Gonzalez-Garcia, Ismael, Roa, Juan, Whittle, Andrew J., Gomez-Santos, Beatriz, Velagapudi, Vidya, Loraine Tung, Y. C., Morgan, Donald A., Voshol, Peter J., Martinez de Morentin, Pablo B., Lopez-Gonzalez, Tania, Linares-Pose, Laura, Gonzalez, Francisco, Chatterjee, Krishna, Sobrino, Tomas, Medina-Gomez, Gema, Davis, Roger J., Casals, Nuria, Oresic, Matej, Coll, Anthony P., Vidal-Puig, Antonio, Mittag, Jens, Tena-Sempere, Manuel, Malagon, Maria M., Dieguez, Carlos, Martinez-Chantar, Maria Luz, Aspichueta, Patricia, Rahmouni, Kamal, Nogueiras, Ruben, Sabio, Guadalupe, Villarroya, Francesc, Lopez, Miguel, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Martinez-Sanchez, Noelia, Seoane-Collazo, Patricia, Contreras, Cristina, Varela, Luis, Villarroya, Joan, Rial-Pensado, Eva, Buque, Xabier, Aurrekoetxea, Igor, Delgado, Teresa C., Vazquez-Martinez, Rafael, Gonzalez-Garcia, Ismael, Roa, Juan, Whittle, Andrew J., Gomez-Santos, Beatriz, Velagapudi, Vidya, Loraine Tung, Y. C., Morgan, Donald A., Voshol, Peter J., Martinez de Morentin, Pablo B., Lopez-Gonzalez, Tania, Linares-Pose, Laura, Gonzalez, Francisco, Chatterjee, Krishna, Sobrino, Tomas, Medina-Gomez, Gema, Davis, Roger J., Casals, Nuria, Oresic, Matej, Coll, Anthony P., Vidal-Puig, Antonio, Mittag, Jens, Tena-Sempere, Manuel, Malagon, Maria M., Dieguez, Carlos, Martinez-Chantar, Maria Luz, Aspichueta, Patricia, Rahmouni, Kamal, Nogueiras, Ruben, Sabio, Guadalupe, Villarroya, Francesc, and Lopez, Miguel

Abstract

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum(ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPK alpha 1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.

Published
2017

43. Deregulated neddylation in liver fibrosis.

Author

Zubiete-Franco, Imanol, Zubiete-Franco, Imanol, Fernández-Tussy, Pablo, Barbier-Torres, Lucía, Simon, Jorge, Fernández-Ramos, David, Lopitz-Otsoa, Fernando, Gutiérrez-de Juan, Virginia, de Davalillo, Sergio López, Duce, Antonio Martín, Iruzubieta, Paula, Taibo, Daniel, Crespo, Javier, Caballeria, Juan, Villa, Erica, Aurrekoetxea, Igor, Aspichueta, Patricia, Varela-Rey, Marta, Lu, Shelly C, Mato, José M, Beraza, Naiara, Delgado, Teresa C, Martínez-Chantar, María L, Zubiete-Franco, Imanol, Zubiete-Franco, Imanol, Fernández-Tussy, Pablo, Barbier-Torres, Lucía, Simon, Jorge, Fernández-Ramos, David, Lopitz-Otsoa, Fernando, Gutiérrez-de Juan, Virginia, de Davalillo, Sergio López, Duce, Antonio Martín, Iruzubieta, Paula, Taibo, Daniel, Crespo, Javier, Caballeria, Juan, Villa, Erica, Aurrekoetxea, Igor, Aspichueta, Patricia, Varela-Rey, Marta, Lu, Shelly C, Mato, José M, Beraza, Naiara, Delgado, Teresa C, and Martínez-Chantar, María L

Abstract

Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances.ConclusionNeddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).

Published
2017

44. Deregulated neddylation in liver fibrosis

Author

Zubiete‐Franco, Imanol, primary, Fernández‐Tussy, Pablo, additional, Barbier‐Torres, Lucía, additional, Simon, Jorge, additional, Fernández‐Ramos, David, additional, Lopitz‐Otsoa, Fernando, additional, Gutiérrez‐de Juan, Virginia, additional, de Davalillo, Sergio López, additional, Duce, Antonio Martín, additional, Iruzubieta, Paula, additional, Taibo, Daniel, additional, Crespo, Javier, additional, Caballeria, Juan, additional, Villa, Erica, additional, Aurrekoetxea, Igor, additional, Aspichueta, Patricia, additional, Varela‐Rey, Marta, additional, Lu, Shelly C, additional, Mato, José M., additional, Beraza, Naiara, additional, Delgado, Teresa C., additional, and Martínez‐Chantar, María L, additional

Published
2016
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45. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

Author

Gomez-Sanchez, Jose A., primary, Carty, Lucy, additional, Iruarrizaga-Lejarreta, Marta, additional, Palomo-Irigoyen, Marta, additional, Varela-Rey, Marta, additional, Griffith, Megan, additional, Hantke, Janina, additional, Macias-Camara, Nuria, additional, Azkargorta, Mikel, additional, Aurrekoetxea, Igor, additional, De Juan, Virginia Gutiérrez, additional, Jefferies, Harold B.J., additional, Aspichueta, Patricia, additional, Elortza, Félix, additional, Aransay, Ana M., additional, Martínez-Chantar, María L., additional, Baas, Frank, additional, Mato, José M., additional, Mirsky, Rhona, additional, Woodhoo, Ashwin, additional, and Jessen, Kristján R., additional

Published
2015
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46. In Vivo Hepatic Triglyceride Secretion Rate in Antisense Oligonucleotide (ASO)-Treated Mice.

Author

Gomez-Santos B, Saenz de Urturi D, Buqué X, Aurrekoetxea I, Nieva A, Fernández-Puertas I, and Aspichueta P

Subjects
Mice, Animals, Triglycerides metabolism, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense metabolism, Liver metabolism, Lipoproteins, VLDL metabolism, Fatty Liver metabolism
Abstract

The liver is a central organ in regulating the whole body metabolic homeostasis, and, among many other processes, it plays a crucial role in lipoprotein metabolism. The liver controls the secretion of very-low-density lipoproteins (VLDLs), particles specialized in the transport of liver lipids, mainly triglycerides (TGs), to the adipose tissue, heart, and muscle, among other tissues, providing fatty acids to be stored or to be used as an energy source. The analysis of this metabolic process provides relevant information about the crosstalk between the liver and other organs. It also helps to identify how the liver is able to secrete lipids to reduce its accumulation. This protocol shows how to analyze the liver TG secretion rate blocking the VLDL clearance from the blood by the administration of poloxamer 407. In addition, it shows how to isolate the VLDL produced by the liver at the end of the experiment, so that the apolipoprotein and lipid content and size can be measured. Using antisense oligonucleotides (ASOs) for silencing target proteins involved in metabolic diseases has emerged as a new promising therapeutic approach. Thus, the usage of ASOs has also been included in this protocol. As a conclusion, evaluation of TG secretion rate in mice provides key information to understand the organ crosstalk in metabolic diseases and the capacity of the liver to secrete lipids to blood., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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47. In Vivo Tissue Lipid Uptake in Antisense Oligonucleotide (ASO)-Treated Mice.

Author

Aurrekoetxea I, Gomez-Santos B, Apodaka-Biguri M, Ruiz de Gauna M, Gonzalez-Romero F, Buqué X, and Aspichueta P

Subjects
Mice, Animals, Triglycerides metabolism, Fatty Acids metabolism, Obesity genetics, Mice, Inbred C57BL, Oligonucleotides, Antisense genetics, Dietary Fats
Abstract

The prevalence of obesity has increased to pandemic levels over the past years. Associated comorbidities linked with the accumulation of lipids in different tissues and blood are responsible for the high mortality in these patients. The increased dietary lipid uptake contributes to these metabolic diseases. Identifying which pathways might be dysregulated in these patients will contribute to find new therapeutic targets. Thus, here, a protocol to follow up the distribution of dietary lipids in blood and tissues is provided. For this, radiolabeled triglyceride in olive oil is administered by oral gavage. To ascertain more precisely the capacity of each tissue for fatty acid uptake, not considering the intestinal barrier, the intravenous (IV) administration of radiolabeled lipids is also described., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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