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4. Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice

Author

Fondevila, Marcos F., Novoa, Eva, Fernandez, Uxia, Dorta, Valentina, Parracho, Tamara, Kreimeyer, Henriette, Garcia-Vence, Maria, Chantada-Vazquez, Maria P., Bravo, Susana B., Porteiro, Begoña, Cabaleiro, Alba, Koning, Mijra, Senra, Ana, Souto, Yara, Verheij, Joanne, Guallar, Diana, Fidalgo, Miguel, Meijnikman, Abraham S., da Silva Lima, Natalia, Dieguez, Carlos, Gonzalez-Rellan, Maria J., and Nogueiras, Ruben

Published
2024
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5. p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway

Author

Fondevila, Marcos F., Novoa, Eva, Gonzalez-Rellan, Maria J., Fernandez, Uxia, Heras, Violeta, Porteiro, Begoña, Parracho, Tamara, Dorta, Valentina, Riobello, Cristina, da Silva Lima, Natalia, Seoane, Samuel, Garcia-Vence, Maria, Chantada-Vazquez, Maria P., Bravo, Susana B., Senra, Ana, Leiva, Magdalena, Marcos, Miguel, Sabio, Guadalupe, Perez-Fernandez, Roman, Dieguez, Carlos, Prevot, Vincent, Schwaninger, Markus, Woodhoo, Ashwin, Martinez-Chantar, Maria L., Schwabe, Robert, Cubero, Francisco J., Varela-Rey, Marta, Crespo, Javier, Iruzubieta, Paula, and Nogueiras, Ruben

Published
2024
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6. Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance

Author

Dragano, Nathalia R.V., Milbank, Edward, Haddad-Tóvolli, Roberta, Garrido-Gil, Pablo, Nóvoa, Eva, Fondevilla, Marcos F., Capelli, Valentina, Zanesco, Ariane Maria, Solon, Carina, Morari, Joseane, Pires, Leticia, Estevez-Salguero, Ánxela, Beiroa, Daniel, González-García, Ismael, Barca-Mayo, Olga, Diéguez, Carlos, Nogueiras, Ruben, Labandeira-García, José L., Rexen Ulven, Elisabeth, Ulven, Trond, Claret, Marc, Velloso, Licio A., and López, Miguel

Published
2024
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9. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Author

Gonzalez-Rellan, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., da Silva Lima, Natalia, Ramos, Lucía, Rodríguez, Amaia, Serrano-Maciá, Marina, Perez-Mejias, Gonzalo, Chantada-Vazquez, Pilar, Riobello, Cristina, Veyrat-Durebex, Christelle, Tovar, Sulay, Coppari, Roberto, Woodhoo, Ashwin, Schwaninger, Markus, Prevot, Vincent, Delgado, Teresa C., Lopez, Miguel, Diaz-Quintana, Antonio, Dieguez, Carlos, Guallar, Diana, Frühbeck, Gema, Diaz-Moreno, Irene, Bravo, Susana B., Martinez-Chantar, Maria L., and Nogueiras, Ruben

Published
2023
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10. Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function

Author

Gonzalez-Rellan, Maria J., Parracho, Tamara, Heras, Violeta, Rodriguez, Amaia, Fondevila, Marcos F., Novoa, Eva, Lima, Natalia, Varela-Rey, Marta, Senra, Ana, Chantada-Vazquez, Maria D.P., Ameneiro, Cristina, Bernardo, Ganeko, Fernandez-Ramos, David, Lopitz-Otsoa, Fernando, Bilbao, Jon, Guallar, Diana, Fidalgo, Miguel, Bravo, Susana, Dieguez, Carlos, Martinez-Chantar, Maria L., Millet, Oscar, Mato, Jose M., Schwaninger, Markus, Prevot, Vincent, Crespo, Javier, Frühbeck, Gema, Iruzubieta, Paula, and Nogueiras, Ruben

Published
2023
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12. Native RNA nanopore sequencing reveals antibiotic-induced loss of rRNA modifications in the A- and P-sites.

Author

Delgado-Tejedor, Anna, Medina, Rebeca, Begik, Oguzhan, Cozzuto, Luca, López, Judith, Blanco, Sandra, Ponomarenko, Julia, and Novoa, Eva Maria

Abstract

The biological relevance and dynamics of mRNA modifications have been extensively studied; however, whether rRNA modifications are dynamically regulated, and under which conditions, remains unclear. Here, we systematically characterize bacterial rRNA modifications upon exposure to diverse antibiotics using native RNA nanopore sequencing. To identify significant rRNA modification changes, we develop NanoConsensus, a novel pipeline that is robust across RNA modification types, stoichiometries and coverage, with very low false positive rates, outperforming all individual algorithms tested. We then apply NanoConsensus to characterize the rRNA modification landscape upon antibiotic exposure, finding that rRNA modification profiles are altered in the vicinity of A and P-sites of the ribosome, in an antibiotic-specific manner, possibly contributing to antibiotic resistance. Our work demonstrates that rRNA modification profiles can be rapidly altered in response to environmental exposures, and provides a robust workflow to study rRNA modification dynamics in any species, in a scalable and reproducible manner. It remains unclear whether rRNA modifications can be naturally altered in response to antibiotics in bacteria. Here, the authors analyzed direct RNA nanopore sequencing data with an analytical pipeline Nanoconsensus, to investigate whether bacterial rRNA modifications are modulated upon exposure to various antibiotics. [ABSTRACT FROM AUTHOR]

Published
2024
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13. GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells.

Author

da Silva Lima, Natália, Cabaleiro, Alba, Novoa, Eva, Riobello, Cristina, Knerr, Patrick J., He, Yantao, Esquinas-Román, Eva M., González-García, Ismael, Prevot, Vincent, Schwaninger, Markus, Dieguez, Carlos, López, Miguel, Müller, Timo D., Varela-Rey, Marta, Douros, Jonathan D., and Nogueiras, Ruben

Abstract

The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control. [ABSTRACT FROM AUTHOR]

Published
2024
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16. 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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20. Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs in Drosophila melanogaster

Author

Sklias, Athena, primary, Cruciani, Sonia, additional, Marchand, Virginie, additional, Spagnuolo, Mariangela, additional, Lavergne, Guillaume, additional, Bourguignon, Valérie, additional, Brambilla, Alessandro, additional, Dreos, René, additional, Marygold, Steven J, additional, Novoa, Eva Maria, additional, Motorin, Yuri, additional, and Roignant, Jean-Yves, additional

Published
2024
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21. Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes

Author

Neafsey, Daniel E, Waterhouse, Robert M, Abai, Mohammad R, Aganezov, Sergey S, Alekseyev, Max A, Allen, James E, Amon, James, Arcà, Bruno, Arensburger, Peter, Artemov, Gleb, Assour, Lauren A, Basseri, Hamidreza, Berlin, Aaron, Birren, Bruce W, Blandin, Stephanie A, Brockman, Andrew I, Burkot, Thomas R, Burt, Austin, Chan, Clara S, Chauve, Cedric, Chiu, Joanna C, Christensen, Mikkel, Costantini, Carlo, Davidson, Victoria LM, Deligianni, Elena, Dottorini, Tania, Dritsou, Vicky, Gabriel, Stacey B, Guelbeogo, Wamdaogo M, Hall, Andrew B, Han, Mira V, Hlaing, Thaung, Hughes, Daniel ST, Jenkins, Adam M, Jiang, Xiaofang, Jungreis, Irwin, Kakani, Evdoxia G, Kamali, Maryam, Kemppainen, Petri, Kennedy, Ryan C, Kirmitzoglou, Ioannis K, Koekemoer, Lizette L, Laban, Njoroge, Langridge, Nicholas, Lawniczak, Mara KN, Lirakis, Manolis, Lobo, Neil F, Lowy, Ernesto, MacCallum, Robert M, Mao, Chunhong, Maslen, Gareth, Mbogo, Charles, McCarthy, Jenny, Michel, Kristin, Mitchell, Sara N, Moore, Wendy, Murphy, Katherine A, Naumenko, Anastasia N, Nolan, Tony, Novoa, Eva M, O'Loughlin, Samantha, Oringanje, Chioma, Oshaghi, Mohammad A, Pakpour, Nazzy, Papathanos, Philippos A, Peery, Ashley N, Povelones, Michael, Prakash, Anil, Price, David P, Rajaraman, Ashok, Reimer, Lisa J, Rinker, David C, Rokas, Antonis, Russell, Tanya L, Sagnon, N'Fale, Sharakhova, Maria V, Shea, Terrance, Simão, Felipe A, Simard, Frederic, Slotman, Michel A, Somboon, Pradya, Stegniy, Vladimir, Struchiner, Claudio J, Thomas, Gregg WC, Tojo, Marta, Topalis, Pantelis, Tubio, José MC, Unger, Maria F, Vontas, John, Walton, Catherine, Wilding, Craig S, Willis, Judith H, Wu, Yi-Chieh, Yan, Guiyun, Zdobnov, Evgeny M, Zhou, Xiaofan, Catteruccia, Flaminia, Christophides, George K, Collins, Frank H, and Cornman, Robert S

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Medical Microbiology, Infectious Diseases, Rare Diseases, Vector-Borne Diseases, Biotechnology, Malaria, Infection, Good Health and Well Being, Animals, Anopheles, Base Sequence, Chromosomes, Insect, Drosophila, Evolution, Molecular, Genome, Insect, Humans, Insect Vectors, Molecular Sequence Data, Phylogeny, Sequence Alignment, General Science & Technology
Abstract

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Published
2015

22. Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes.

Author

Neafsey, Daniel E, Waterhouse, Robert M, Abai, Mohammad R, Aganezov, Sergey S, Alekseyev, Max A, Allen, James E, Amon, James, Arcà, Bruno, Arensburger, Peter, Artemov, Gleb, Assour, Lauren A, Basseri, Hamidreza, Berlin, Aaron, Birren, Bruce W, Blandin, Stephanie A, Brockman, Andrew I, Burkot, Thomas R, Burt, Austin, Chan, Clara S, Chauve, Cedric, Chiu, Joanna C, Christensen, Mikkel, Costantini, Carlo, Davidson, Victoria LM, Deligianni, Elena, Dottorini, Tania, Dritsou, Vicky, Gabriel, Stacey B, Guelbeogo, Wamdaogo M, Hall, Andrew B, Han, Mira V, Hlaing, Thaung, Hughes, Daniel ST, Jenkins, Adam M, Jiang, Xiaofang, Jungreis, Irwin, Kakani, Evdoxia G, Kamali, Maryam, Kemppainen, Petri, Kennedy, Ryan C, Kirmitzoglou, Ioannis K, Koekemoer, Lizette L, Laban, Njoroge, Langridge, Nicholas, Lawniczak, Mara KN, Lirakis, Manolis, Lobo, Neil F, Lowy, Ernesto, MacCallum, Robert M, Mao, Chunhong, Maslen, Gareth, Mbogo, Charles, McCarthy, Jenny, Michel, Kristin, Mitchell, Sara N, Moore, Wendy, Murphy, Katherine A, Naumenko, Anastasia N, Nolan, Tony, Novoa, Eva M, O'Loughlin, Samantha, Oringanje, Chioma, Oshaghi, Mohammad A, Pakpour, Nazzy, Papathanos, Philippos A, Peery, Ashley N, Povelones, Michael, Prakash, Anil, Price, David P, Rajaraman, Ashok, Reimer, Lisa J, Rinker, David C, Rokas, Antonis, Russell, Tanya L, Sagnon, N'Fale, Sharakhova, Maria V, Shea, Terrance, Simão, Felipe A, Simard, Frederic, Slotman, Michel A, Somboon, Pradya, Stegniy, Vladimir, Struchiner, Claudio J, Thomas, Gregg WC, Tojo, Marta, Topalis, Pantelis, Tubio, José MC, Unger, Maria F, Vontas, John, Walton, Catherine, Wilding, Craig S, Willis, Judith H, Wu, Yi-Chieh, Yan, Guiyun, Zdobnov, Evgeny M, Zhou, Xiaofan, Catteruccia, Flaminia, Christophides, George K, Collins, Frank H, and Cornman, Robert S

Subjects
Animals, Humans, Anopheles, Drosophila, Malaria, Sequence Alignment, Insect Vectors, Evolution, Molecular, Phylogeny, Base Sequence, Molecular Sequence Data, Genome, Insect, Chromosomes, Insect, Evolution, Molecular, Genome, Insect, Chromosomes, General Science & Technology
Abstract

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Published
2015

24. O-GlcNAcylated p53 in the liver modulates hepatic glucose production

Author

Gonzalez-Rellan, Maria J., Fondevila, Marcos F., Fernandez, Uxia, Rodríguez, Amaia, Varela-Rey, Marta, Veyrat-Durebex, Christelle, Seoane, Samuel, Bernardo, Ganeko, Lopitz-Otsoa, Fernando, Fernández-Ramos, David, Bilbao, Jon, Iglesias, Cristina, Novoa, Eva, Ameneiro, Cristina, Senra, Ana, Beiroa, Daniel, Cuñarro, Juan, DP Chantada-Vazquez, Maria, Garcia-Vence, Maria, Bravo, Susana B., Da Silva Lima, Natalia, Porteiro, Begoña, Carneiro, Carmen, Vidal, Anxo, Tovar, Sulay, Müller, Timo D., Ferno, Johan, Guallar, Diana, Fidalgo, Miguel, Sabio, Guadalupe, Herzig, Stephan, Yang, Won Ho, Cho, Jin Won, Martinez-Chantar, Maria Luz, Perez-Fernandez, Roman, López, Miguel, Dieguez, Carlos, Mato, Jose M., Millet, Oscar, Coppari, Roberto, Woodhoo, Ashwin, Fruhbeck, Gema, and Nogueiras, Ruben

Published
2021
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31. N6-methyladenosine modification is not a general trait of viral RNA genomes.

Author

Baquero-Pérez, Belinda, Yonchev, Ivaylo D., Delgado-Tejedor, Anna, Medina, Rebeca, Puig-Torrents, Mireia, Sudbery, Ian, Begik, Oguzhan, Wilson, Stuart A., Novoa, Eva Maria, and Díez, Juana

Abstract

Despite the nuclear localization of the m6A machinery, the genomes of multiple exclusively-cytoplasmic RNA viruses, such as chikungunya (CHIKV) and dengue (DENV), are reported to be extensively m6A-modified. However, these findings are mostly based on m6A-Seq, an antibody-dependent technique with a high rate of false positives. Here, we address the presence of m6A in CHIKV and DENV RNAs. For this, we combine m6A-Seq and the antibody-independent SELECT and nanopore direct RNA sequencing techniques with functional, molecular, and mutagenesis studies. Following this comprehensive analysis, we find no evidence of m6A modification in CHIKV or DENV transcripts. Furthermore, depletion of key components of the host m6A machinery does not affect CHIKV or DENV infection. Moreover, CHIKV or DENV infection has no effect on the m6A machinery’s localization. Our results challenge the prevailing notion that m6A modification is a general feature of cytoplasmic RNA viruses and underscore the importance of validating RNA modifications with orthogonal approaches.A comprehensive analysis found no evidence of m6A modifications in the genome of the cytoplasmic RNA viruses CHIKV and DENV, challenging the current notion that m6A modification is a general feature of cytoplasmic RNA viruses. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Xunta de Galicia, European Community (EC), González Rellán, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., Da Silva Lima, Natalia, Rodríguez, Amaia, Pérez Mejías, Gonzalo, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, Nogueiras, Rubén, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Xunta de Galicia, European Community (EC), González Rellán, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., Da Silva Lima, Natalia, Rodríguez, Amaia, Pérez Mejías, Gonzalo, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, and Nogueiras, Rubén

Abstract

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Published
2023

36. Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Gonzalez-Rellan, Maria J., Parracho, Tamara, Heras, Violeta, Rodriguez, Amaia, Fondevila, Marcos F., Novoa, Eva, Lima, Natalia, Varela-Rey, Marta, Senra, Ana, Chantada-Vazquez, Maria D.P., Ameneiro, Cristina, Bernardo, Ganeko, Fernandez-Ramos, David, Lopitz-Otsoa, Fernando, Bilbao, Jon, Guallar, Diana, Fidalgo, Miguel, Bravo, Susana, Dieguez, Carlos, Martinez-Chantar, Maria L., Millet, Oscar, Mato, Jose M., Schwaninger, Markus, Prevot, Vincent, Crespo, Javier, Frühbeck, Gema, Iruzubieta, Paula, Nogueiras, Ruben, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Gonzalez-Rellan, Maria J., Parracho, Tamara, Heras, Violeta, Rodriguez, Amaia, Fondevila, Marcos F., Novoa, Eva, Lima, Natalia, Varela-Rey, Marta, Senra, Ana, Chantada-Vazquez, Maria D.P., Ameneiro, Cristina, Bernardo, Ganeko, Fernandez-Ramos, David, Lopitz-Otsoa, Fernando, Bilbao, Jon, Guallar, Diana, Fidalgo, Miguel, Bravo, Susana, Dieguez, Carlos, Martinez-Chantar, Maria L., Millet, Oscar, Mato, Jose M., Schwaninger, Markus, Prevot, Vincent, Crespo, Javier, Frühbeck, Gema, Iruzubieta, Paula, and Nogueiras, Ruben

Abstract

Objective O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. Methods We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. Results O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. Conclusions These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation

Published
2023

37. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Author

Agencia Estatal de Investigación (España), Ministerio de Ciencia y Tecnología (España), Xunta de Galicia, Fundación BBVA, Fundación Atresmedia, Fundación la Caixa, European Commission, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Instituto de Salud Carlos III, Gonzalez-Rellan, María J, Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F, da Silva Lima, Natalia, Ramos, Lucía, Rodríguez, Amaia, Serrano-Maciá, Marina, Perez-Mejias, Gonzalo, Chantada-Vazquez, Pilar, Riobello, Cristina, Veyrat-Durebex, Christelle, Tovar, Sulay, Coppari, Roberto, Woodhoo, Ashwin, Schwaninger, Markus, Prevot, Vincent, Delgado, Teresa C, Lopez, Miguel, Diaz-Quintana, Antonio, Dieguez, Carlos, Guallar, Diana, Frühbeck, Gema, Diaz-Moreno, Irene, Bravo, Susana B, Martinez-Chantar, Maria L, Nogueiras, Ruben, Agencia Estatal de Investigación (España), Ministerio de Ciencia y Tecnología (España), Xunta de Galicia, Fundación BBVA, Fundación Atresmedia, Fundación la Caixa, European Commission, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Instituto de Salud Carlos III, Gonzalez-Rellan, María J, Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F, da Silva Lima, Natalia, Ramos, Lucía, Rodríguez, Amaia, Serrano-Maciá, Marina, Perez-Mejias, Gonzalo, Chantada-Vazquez, Pilar, Riobello, Cristina, Veyrat-Durebex, Christelle, Tovar, Sulay, Coppari, Roberto, Woodhoo, Ashwin, Schwaninger, Markus, Prevot, Vincent, Delgado, Teresa C, Lopez, Miguel, Diaz-Quintana, Antonio, Dieguez, Carlos, Guallar, Diana, Frühbeck, Gema, Diaz-Moreno, Irene, Bravo, Susana B, Martinez-Chantar, Maria L, and Nogueiras, Ruben

Abstract

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Published
2023

40. Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart

Author

Milenkovic, Ivan, primary, Santos Vieira, Helaine Graziele, additional, Lucas, Morghan C, additional, Ruiz-Orera, Jorge, additional, Patone, Giannino, additional, Kesteven, Scott, additional, Wu, Jianxin, additional, Feneley, Michael, additional, Espadas, Guadalupe, additional, Sabidó, Eduard, additional, Hübner, Norbert, additional, van Heesch, Sebastiaan, additional, Völkers, Mirko, additional, and Novoa, Eva Maria, additional

Published
2023
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41. p63 Controls Metabolic Activation of Hepatic Stellate Cells and Fibrosis via ACC1

Author

Fondevila, Marcos, primary, Novoa, Eva María, additional, Gonzalez-Rellan, Maria Jesús, additional, Fernandez, Uxia, additional, Heras, Violeta, additional, Porteiro, Begoña, additional, Parracho, Tamara, additional, Varela-Rey, Marta, additional, Dorta, Valentina, additional, Silva, Natalia da, additional, Seoane, Samuel, additional, Garcia-Vence, Maria, additional, Chantada-Vazquez, Maria, additional, Bravo, Susana, additional, Senra, Ana, additional, Leiva, Magdalena, additional, Marcos, Miguel, additional, Sabio, Guadalupe, additional, Perez-Fernandez, Roman, additional, Dieguez, Carlos, additional, Prevot, Vincent, additional, Schwaninger, Markus, additional, Martinez-Chantar, Maria, additional, Schwabe, Robert, additional, Cubero, Francisco, additional, Crespo, Javier, additional, Iruzubieta, Paula, additional, and Nogueiras, Ruben, additional

Published
2023
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44. Nano3P-seq: transcriptome-wide analysis of gene expression and tail dynamics using end-capture nanopore cDNA sequencing

Author

Begik, Oguzhan, primary, Diensthuber, Gregor, additional, Liu, Huanle, additional, Delgado-Tejedor, Anna, additional, Kontur, Cassandra, additional, Niazi, Adnan Muhammad, additional, Valen, Eivind, additional, Giraldez, Antonio J., additional, Beaudoin, Jean-Denis, additional, Mattick, John S., additional, and Novoa, Eva Maria, additional

Published
2022
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47. Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis

Author

Fondevila, Marcos F., primary, Fernandez, Uxia, additional, Heras, Violeta, additional, Parracho, Tamara, additional, Gonzalez-Rellan, Maria J., additional, Novoa, Eva, additional, Porteiro, Begoña, additional, Alonso, Cristina, additional, Mayo, Rebeca, additional, da Silva Lima, Natalia, additional, Iglesias, Cristina, additional, Filliol, Aveline A., additional, Senra, Ana, additional, Delgado, Teresa C., additional, Woodhoo, Ashwin, additional, Herrero, Laura, additional, Serra, Dolors, additional, Prevot, Vincent, additional, Schwaninger, Markus, additional, López, Miguel, additional, Dieguez, Carlos, additional, Millet, Oscar, additional, Mato, Jose M., additional, Cubero, Francisco J., additional, Varela-Rey, Marta, additional, Iruzubieta, Paula, additional, Crespo, Javier, additional, Martinez-Chantar, Maria L., additional, Schwabe, Robert F., additional, and Nogueiras, Ruben, additional

Published
2022
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48. 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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50. Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

Author

Fisiología, Fisiologia, Da Silva Lima, Natalia, Fondevila, Marcos F., Novoa, Eva, Buqué García, Xabier, Mercado Gómez, María, Gallet, Sarah, González Rellán, María Jesús, Fernández, Uxia, Loyens, Anne, García Vence, María, Chantada Vázquez, María del Pilar, Bravo López, Susana Belén, Marañón, Patricia, Senra, Ana, Escudero González, Adriana, Leiva, Magdalena, Guallar, Diana, Fidalgo, Miguel, Gomes, Pedro, Claret, Marc, Sabio, Guadalupe, Varela Rey, Marta, Cardoso Delgado, Teresa de Jesús, Montero Vallejo, Rocío, Ampuero Herrojo, Javier, López, Miguel, Diéguez González, Carlos, Herrero, Laura, Serra, Dolors, Schwaninger, Markus, Prevot, Vincent, Gallego Durán, Rocío, Romero Gómez, Manuel, Iruzubieta, Paula, Crespo, Javier, Martínez Chantar, María Luz, García Monzón, Carmelo, González Rodríguez, Águeda, Aspichueta Celaá, Patricia, Nogueiras Pozo, Rubén, Fisiología, Fisiologia, Da Silva Lima, Natalia, Fondevila, Marcos F., Novoa, Eva, Buqué García, Xabier, Mercado Gómez, María, Gallet, Sarah, González Rellán, María Jesús, Fernández, Uxia, Loyens, Anne, García Vence, María, Chantada Vázquez, María del Pilar, Bravo López, Susana Belén, Marañón, Patricia, Senra, Ana, Escudero González, Adriana, Leiva, Magdalena, Guallar, Diana, Fidalgo, Miguel, Gomes, Pedro, Claret, Marc, Sabio, Guadalupe, Varela Rey, Marta, Cardoso Delgado, Teresa de Jesús, Montero Vallejo, Rocío, Ampuero Herrojo, Javier, López, Miguel, Diéguez González, Carlos, Herrero, Laura, Serra, Dolors, Schwaninger, Markus, Prevot, Vincent, Gallego Durán, Rocío, Romero Gómez, Manuel, Iruzubieta, Paula, Crespo, Javier, Martínez Chantar, María Luz, García Monzón, Carmelo, González Rodríguez, Águeda, Aspichueta Celaá, Patricia, and Nogueiras Pozo, Rubén

Abstract

[EN]Background & Aims: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. Methods: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. Results: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and nonalcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63-and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. Conclusions: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. Lay summary: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease

Published
2022

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