23 results on '"Aurrekoetxea, Igor"'
Search Results
2. Role of Aramchol in steatohepatitis and fibrosis in mice.
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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
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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.
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- 2017
3. Deregulated neddylation in liver fibrosis
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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
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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).
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- 2017
4. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
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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
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- 2017
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5. Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity
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Hamidi, Mohaddase, primary, Eriz, Ainhoa, additional, Mitxelena, Jone, additional, Fernandez-Ares, Larraitz, additional, Aurrekoetxea, Igor, additional, Aspichueta, Patricia, additional, Iglesias-Ara, Ainhoa, additional, and Zubiaga, Ana M., additional
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- 2022
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6. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids
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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.
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- 2022
7. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids
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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.
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- 2022
8. Serum oxidizability and antioxidant status in patients undergoing in vitro fertilization
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Aurrekoetxea, Igor, Ruiz-Sanz, José Ignacio, del Agua, Ainhoa Ruiz, Navarro, Rosaura, Hernández, M. Luisa, Matorras, Roberto, Prieto, Begoña, and Ruiz-Larrea, M. Begoña
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- 2010
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9. E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment
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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.
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- 2021
10. E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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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
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- 2021
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11. Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease
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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.
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- 2020
12. Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease
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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
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- 2020
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13. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
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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.
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- 2024
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14. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models
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Dervan Peter A, Shelly Martin J, Aurrekoetxea Igor, Blanco Alfonso, Cottell David C, Hudson Lance, Donatello Simona, Kell Malcolm R, Stokes Maurice, Hill Arnold DK, and Hopkins Ann M
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.
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- 2011
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15. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
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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
16. Deregulated neddylation in liver fibrosis.
- Author
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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
17. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves
- Author
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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
- Full Text
- View/download PDF
18. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.
- Author
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Donatello, Simona, Hudson, Lance, Cottell, David C, Blanco, Alfonso, Aurrekoetxea, Igor, Shelly, Martin J, Dervan, Peter A, Kell, Malcolm R, Stokes, Maurice, Hill, Arnold D K, Hopkins, Ann M, Donatello, Simona, Hudson, Lance, Cottell, David C, Blanco, Alfonso, Aurrekoetxea, Igor, Shelly, Martin J, Dervan, Peter A, Kell, Malcolm R, Stokes, Maurice, Hill, Arnold D K, and Hopkins, Ann M
- Abstract
Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
- Published
- 2011
19. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models
- Author
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Donatello, Simona, primary, Hudson, Lance, additional, Cottell, David C, additional, Blanco, Alfonso, additional, Aurrekoetxea, Igor, additional, Shelly, Martin J, additional, Dervan, Peter A, additional, Kell, Malcolm R, additional, Stokes, Maurice, additional, Hill, Arnold DK, additional, and Hopkins, Ann M, additional
- Published
- 2011
- Full Text
- View/download PDF
20. Ala16Val SOD2 polymorphism is associated with higher pregnancy rates in in vitro fertilization cycles
- Author
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Ruiz-Sanz, José Ignacio, primary, Aurrekoetxea, Igor, additional, Matorras, Roberto, additional, and Ruiz-Larrea, M. Begoña, additional
- Published
- 2011
- Full Text
- View/download PDF
21. Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12
- Author
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Crettaz, Julien, primary, Otano, Itziar, additional, Ochoa, Laura, additional, Benito, Alberto, additional, Paneda, Astrid, additional, Aurrekoetxea, Igor, additional, Berraondo, Pedro, additional, Rodríguez-Madoz, Juan Roberto, additional, Astudillo, Aurora, additional, Kreppel, Florian, additional, Kochanek, Stefan, additional, Ruiz, Juan, additional, Menne, Stephan, additional, Prieto, Jesus, additional, and Gonzalez-Aseguinolaza, Gloria, additional
- Published
- 2009
- Full Text
- View/download PDF
22. Role of aramchol in steatohepatitis and fibrosis in mice
- Author
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Iruarrizaga‐Lejarreta, Marta, Varela‐Rey, Marta, Fernández‐Ramos, David, Martínez‐Arranz, Ibon, Delgado, Teresa C, Simon, Jorge, Gutiérrez‐de Juan, Virginia, delaCruz‐Villar, Laura, Azkargorta, Mikel, Lavin, José L., Mayo, Rebeca, Van Liempd, Sebastiaan M., Aurrekoetxea, Igor, Buqué, Xabier, Delle Cave, Donatella, Peña, Arantza, Rodríguez‐Cuesta, Juan, Aransay, Ana M., Elortza, Félix, Falcón‐Pérez, Juan Manuel, Aspichueta, Patricia, Hayardeny, Liat, Noureddin, Mazen, Sanyal, Arun, Alonso, Cristina, Anguita, Juan, Martínez‐Chantar, María Luz, Lu, Shelly C., and Mato, José M.
- Subjects
nutritional and metabolic diseases ,3. Good health - Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that 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. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present 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 an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap.Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 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 patients with NAFLD, which supports the potential use of Aramchol in NASH treatment.
23. Role of aramchol in steatohepatitis and fibrosis in mice
- Author
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Iruarrizaga‐Lejarreta, Marta, Varela‐Rey, Marta, Fernández‐Ramos, David, Martínez‐Arranz, Ibon, Delgado, Teresa C, Simon, Jorge, Gutiérrez‐de Juan, Virginia, delaCruz‐Villar, Laura, Azkargorta, Mikel, Lavin, José L., Mayo, Rebeca, Van Liempd, Sebastiaan M., Aurrekoetxea, Igor, Buqué, Xabier, Delle Cave, Donatella, Peña, Arantza, Rodríguez‐Cuesta, Juan, Aransay, Ana M., Elortza, Félix, Falcón‐Pérez, Juan Manuel, Aspichueta, Patricia, Hayardeny, Liat, Noureddin, Mazen, Sanyal, Arun, Alonso, Cristina, Anguita, Juan, Martínez‐Chantar, María Luz, Lu, Shelly C., and Mato, José M.
- Subjects
nutritional and metabolic diseases ,3. Good health - Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that 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. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present 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 an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 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 patients with NAFLD, which supports the potential use of Aramchol in NASH treatment.
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