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1. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting

Author

Capelo-Diz, Alba, Lachiondo-Ortega, Sofía, Fernández-Ramos, David, Cañas-Martín, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, González-Rellan, Maria J., Mosca, Laura, Blazquez-Vicens, Joan, Tinahones-Ruano, Alberto, Fondevila, Marcos F., Buyan, Mason, Delgado, Teresa C., Gutierrez de Juan, Virginia, Ayuso-García, Paula, Sánchez-Rueda, Alejandro, Velasco-Avilés, Sergio, Fernández-Susavila, Héctor, Riobello-Suárez, Cristina, Dziechciarz, Bartlomiej, Montiel-Duarte, Cristina, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Bilbao-García, Jon, Bernardo-Seisdedos, Ganeko, Senra, Ana, Soriano-Navarro, Mario, Millet, Oscar, Díaz-Lagares, Ángel, Crujeiras, Ana B., Bao-Caamano, Aida, Cabrera, Diana, van Liempd, Sebastiaan, Tamayo-Caro, Miguel, Borzacchiello, Luigi, Gomez-Santos, Beatriz, Buqué, Xabier, Sáenz de Urturi, Diego, González-Romero, Francisco, Simon, Jorge, Rodríguez-Agudo, Rubén, Ruiz, Asier, Matute, Carlos, Beiroa, Daniel, Falcon-Perez, Juan M., Aspichueta, Patricia, Rodríguez-Cuesta, Juan, Porcelli, Marina, Pajares, María A., Ameneiro, Cristina, Fidalgo, Miguel, Aransay, Ana M., Lama-Díaz, Tomas, Blanco, Miguel G., López, Miguel, Villa-Bellosta, Ricardo, Müller, Timo D., Nogueiras, Rubén, Woodhoo, Ashwin, Martínez-Chantar, María Luz, and Varela-Rey, Marta

Published
2023
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2. 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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4. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH

Author

Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez-de-Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernandez-Rodriguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Delgado, Teresa Cardoso, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz

Published
2021
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5. 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

6. 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

7. 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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8. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Serrano Maciá, Marina, Simón, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz Otsoa, Fernando, Sáenz de Urturi, Diego, Rodríguez Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga-Uribiarte, Maider, Fernández-Ramos, David, Buqué, Xabier, Baselli, Guido Alessandro, Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus, Avila, Matias A., Marin, Jose, Aspichueta, Patricia, Sutherland, James D., Barrio, Rosa, Mayor, Ugo, Elortza, Felix, Xirodimas, Dimitris, Nogueiras Pozo, Rubén, Delgado, Teresa, Martinez Chantar, Maria Luz, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Serrano Maciá, Marina, Simón, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz Otsoa, Fernando, Sáenz de Urturi, Diego, Rodríguez Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga-Uribiarte, Maider, Fernández-Ramos, David, Buqué, Xabier, Baselli, Guido Alessandro, Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus, Avila, Matias A., Marin, Jose, Aspichueta, Patricia, Sutherland, James D., Barrio, Rosa, Mayor, Ugo, Elortza, Felix, Xirodimas, Dimitris, Nogueiras Pozo, Rubén, Delgado, Teresa, and Martinez Chantar, Maria Luz

Abstract

Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models. Conclusions: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD

Published
2021

9. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz

Abstract

Background & Aims: Perturbations of intracellular magnesium (Mg) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Methods: Serum Mg levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. Results: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Lay summary: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

Published
2021

10. MCJ: A therapeutic target in hepatic ischemia and reperfusion injury

Author

Goikoetxea-Usandizaga, Naroa, Fernández-Ramos, David, Serrano-Maciá, Marina, Eugenia Cornide, Maria, Jimenez-Castro, Monica, Alfano, Bennedetta, Sáenz de Urturi, Diego, Gonzalez-Romero, Francisco, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Cardoso Delgado, Teresa, Lopitz-Otsoa, Fernando, Barbier Torres, Lucia, Fernández-Tussy, Pablo, Simón, Jorge, Martín, Paloma, Anguita, Juan, Perez Redondo, Marina, Miñambres, Eduardo, Lu, Shelly C., Mato, José M., Sabio, Guadalupe, Peralta, Carmen, Aspichueta, Patricia, Casado, Marta, Martín, César, Varela-Rey, Marta, and Martínez-Chantar, María Luz

Abstract

Trabajo presentado en The International Liver Congress, celebrado en Viena (Austria) del 10 al 14 de abril de 2019., [Background and aims]: Ischemia/reperfusion (IR) injury, a frequent pathological process during liver resection, is a leading cause of post transplantation organ dysfunction. The extent of the injury can determine the success of the procedure and the survival of the patient. Therefore, attenuation of pathology caused by the injury and improving liver function after the procedure would be critical for clinicians to diminish IR injury prevalence and improve the outcome. Mitochondria play a key role in liver homeostasis; indeed, more functional mitochondria induce hepatic regeneration. MCJ, also known as DNACJ15, is an endogenous negative regulator of complex I, located in the mitochondrial electron transport chain. While under normal conditions MCJ deficiency does not result in an altered phenotype in mice, its absence improves mitochondrial activity without increasing mitochondrial ROS. We present MCJ as a new target to minimize hepatic damage caused by IR injury and enhance the efficiency of liver regeneration during liver resection., [Method]: Partial hepatectomies (PH) and PH combined with IR injuries were performed in MCJ-KO mice and in WT mice after MCJ silencing., [Results]: We observed that the lack of MCJ reduced liver damage and induced hepatic regeneration after IR injury; MCJ-KO mice showed lower levels of Caspase 3 and a significantly higher Cyclin D1 expression. Moreover, we saw an improved metabolic response to hepatic insufficiency and an accelerated cell cycle progression during liver resection, which led to a faster recovery of the hepatic mass. In the initial phase after the PH, glucagon response was amplified in MCJ-KO mice, characterized by increased cAMP and AKT signaling, along with higher Ca+2 release from the endoplasmic reticulum (ER), glycogen synthase kinase (GSK-3beta) inhibition and nuclear factorKbeta (NFKbeta) translocation to the nucleus. In the proliferative phase, ablation of MCJ accelerated the induction of proliferative markers. Indeed, after MCJ silencing, an improved phenotype was detected in an aging mice model that underwent partial hepatectomy. Hepatic insufficiency was ameliorated, PCNA expression increased and steatosis reverted. Importantly, the combined procedure of PH and IR injury that resemble liver transplant procedure resulted in a 100% survival rate for MCJ-KO mice while just the 33% of MCJ-WT mice survived the operation. Increased levels of MCJ were found in liver biopsies from all liver donors at 60 minutes after normothermic regional perfusion (nRP) was started., [Conclusion]: Overall, MCJ silencing during liver resection emerges as a promising therapy for IR injury and restoration of hepatic mass.

Published
2019

11. 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

12. Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice.

Author

Cabreraa, Daniel, Raoa, Isabel, Raasch, Fabiola, Solis, Nancy, Pizarro, Margarita, Freire, Mariela, Sáenz De Urturi, Diego, Ramírez, Carolina A., Triantafilo, Nicolás, León, Jonathan, Riquelme, Arnoldo, Barrera, Francisco, Baudrand, Rene, Aspichueta, Patricia, Arrese, Marco, and Arab, Juan P.

Subjects
MINERALOCORTICOID receptors, NON-alcoholic fatty liver disease, SODIUM, CHOLINE, LABORATORY mice, LIVER histology
Abstract

Introduction and Objectives: Nonalcoholic-fatty-liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS). Mineralocorticoid receptor (MR) activation is associated with increased risk of MetS but few studies have assessed the role of liver MR on NAFLD. We aimed to evaluate the effect of MR modulation by sodium intake in liver injury in experimental models of NAFLD. Materials and Methods: C57BL/6J mice were fed either a high-fat-diet (HFD) or a choline/methionine deficient (MCD) diet with different sodium concentrations. Hepatic concentration of lipid species, serum aldosterone levels, expression of MR, proinflammatory and profibrotic markers and liver histology were assessed. Results: Mice fed with High-Na+/HFD showed a lower MR expression in liver (p = 0.01) and less steatosis on histology (p = 0.04). Consistently, animals from this group exhibited lower levels of serum aldosterone (p = 0.028) and lower hepatic triglyceride content (p = 0.008). This associated to a reduced expression of lipogenic genes, significant changes in lipid subspecies, lower HOMA-IR (p < 0.05), and lower expression of pro-inflammatory and profibrotic markers compared to those mice fed a Low-Na+/HFD. Additionally, mice fed a High-Na+/HFD showed higher expression of salt-inducible kinase (SIK)-1 and lower expression of serum-and-glucocorticoid-inducible kinase (SGK)-1. Similar results were observed with the MCD diet model. Conclusion: We identified in two experimental models of NAFLD that High-Na+ diet content is associated to lower serum aldosterone levels and hepatic MR downregulation, associated to decreased steatosis and reduced de novo hepatic lipogenesis, proinflammatory and profibrotic markers. Decreased activation of hepatic MR seems to generate beneficial downstream inhibition of lipogenesis in experimental NAFLD. [ABSTRACT FROM AUTHOR]

Published
2021
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