Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis
Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. Methods: CDKN1A expression...
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2025-01-01
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| author | Arantza Lamas-Paz Alejandro Hionides-Gutiérrez Feifei Guo Gonzalo Jorquera Laura Morán-Blanco Raquel Benedé-Ubieto Mariana Mesquita Olga Estévez-Vázquez Kang Zheng Marina Mazariegos Elena Vázquez-Ogando Elena Blázquez-López Iris Asensio Beste Mutlu Beatriz Gomez-Santos María Isabel Peligros Javier Vaquero Rafael Bañares Teresa C. Delgado María Luz Martínez-Chantar Eduardo Martínez-Naves Carlos Sanz-García Mohamed Ramadan Mohamed Sofía Tesolato Pilar Iniesta Rocío Gallego-Durán Douglas Maya-Miles Javier Ampuero Manuel Romero-Gómez Ana Martínez-Alcocer David Sanfeliu-Redondo Anabel Fernández-Iglesias Jordi Gracia-Sancho Mar Coll Isabel Graupera Pere Ginès Andrea Ciudin Jesús Rivera-Esteban Juan M. Pericàs Matías A. Ávila Maria Dolores Frutos Carlos Manuel Martínez-Cáceres Bruno Ramos-Molina Patricia Aspichueta Pere Puigserver Yulia A. Nevzorova Francisco Javier Cubero |
| author_facet | Arantza Lamas-Paz Alejandro Hionides-Gutiérrez Feifei Guo Gonzalo Jorquera Laura Morán-Blanco Raquel Benedé-Ubieto Mariana Mesquita Olga Estévez-Vázquez Kang Zheng Marina Mazariegos Elena Vázquez-Ogando Elena Blázquez-López Iris Asensio Beste Mutlu Beatriz Gomez-Santos María Isabel Peligros Javier Vaquero Rafael Bañares Teresa C. Delgado María Luz Martínez-Chantar Eduardo Martínez-Naves Carlos Sanz-García Mohamed Ramadan Mohamed Sofía Tesolato Pilar Iniesta Rocío Gallego-Durán Douglas Maya-Miles Javier Ampuero Manuel Romero-Gómez Ana Martínez-Alcocer David Sanfeliu-Redondo Anabel Fernández-Iglesias Jordi Gracia-Sancho Mar Coll Isabel Graupera Pere Ginès Andrea Ciudin Jesús Rivera-Esteban Juan M. Pericàs Matías A. Ávila Maria Dolores Frutos Carlos Manuel Martínez-Cáceres Bruno Ramos-Molina Patricia Aspichueta Pere Puigserver Yulia A. Nevzorova Francisco Javier Cubero |
| author_sort | Arantza Lamas-Paz |
| collection | DOAJ |
| description | Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. Methods: CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed. Results: A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. Conclusions: Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption. Impact and implications:: Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption. |
| format | Article |
| id | doaj-art-4e2f28ede80d4cfa8f3201c467cc1073 |
| institution | OA Journals |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj-art-4e2f28ede80d4cfa8f3201c467cc10732025-08-20T02:27:41ZengElsevierJHEP Reports2589-55592025-01-017110123010.1016/j.jhepr.2024.101230Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasisArantza Lamas-Paz0Alejandro Hionides-Gutiérrez1Feifei Guo2Gonzalo Jorquera3Laura Morán-Blanco4Raquel Benedé-Ubieto5Mariana Mesquita6Olga Estévez-Vázquez7Kang Zheng8Marina Mazariegos9Elena Vázquez-Ogando10Elena Blázquez-López11Iris Asensio12Beste Mutlu13Beatriz Gomez-Santos14María Isabel Peligros15Javier Vaquero16Rafael Bañares17Teresa C. Delgado18María Luz Martínez-Chantar19Eduardo Martínez-Naves20Carlos Sanz-García21Mohamed Ramadan Mohamed22Sofía Tesolato23Pilar Iniesta24Rocío Gallego-Durán25Douglas Maya-Miles26Javier Ampuero27Manuel Romero-Gómez28Ana Martínez-Alcocer29David Sanfeliu-Redondo30Anabel Fernández-Iglesias31Jordi Gracia-Sancho32Mar Coll33Isabel Graupera34Pere Ginès35Andrea Ciudin36Jesús Rivera-Esteban37Juan M. Pericàs38Matías A. Ávila39Maria Dolores Frutos40Carlos Manuel Martínez-Cáceres41Bruno Ramos-Molina42Patricia Aspichueta43Pere Puigserver44Yulia A. Nevzorova45Francisco Javier Cubero46Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; 12 de Octubre Health Research Institute (imas12), Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Department of Obstetrics and Gynaecology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaInstitute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile; Physiology Institute, Science Faculty, Universidad de Valparaíso, Valparaíso, ChileDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; State University of Campinas, Campinas, Sao Paulo, BrazilDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Department of Anesthesiology, Nanjing Pukou District Hospital of Chinese Medicine Central Laboratory Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainServicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainServicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainServicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USADepartment of Physiology, Basque Country University (UPV/EHU) School of Medicine and Nursing, Bilbao, Spain; Biobizkaia Health Institute, Barakaldo, SpainServicio de Anatomía Patológica Hospital General Universitario Gregorio Marañón Madrid, SpainServicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainServicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainLiver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; 12 de Octubre Health Research Institute (imas12), Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, SpainDepartment of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, GermanyDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain; San Carlos Health Research Institute (IdISSC), Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain; San Carlos Health Research Institute (IdISSC), Madrid, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clinic, Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clinic, Barcelona, SpainEndocrinology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain; Centre for Biomedical Research, Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, SpainLiver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain; Puerta de Hierro University Hospital, Instituto de Investigación Sanitaria Puerta de Hierro, Majadahonda, Madrid, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Hepatology Laboratory, Solid Tumors Program, CIMA, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, SpainDepartment of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, SpainExperimental Pathology Service, Biomedical Research Institute of Murcia (IMIB), Murcia, SpainLaboratorio de Obesidad y Metabolismo, Instituto de Investigación Biomédica de Murcia (IMIB-Arrixaca), Murcia, SpainCentre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Department of Physiology, Basque Country University (UPV/EHU) School of Medicine and Nursing, Bilbao, Spain; Biobizkaia Health Institute, Barakaldo, SpainDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USADepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain; Corresponding author. Address: Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, c/Doctor Severo Ochoa, 9, 28040, Madrid, Spain. Tel.: +34 91394 1385.Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. Methods: CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed. Results: A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. Conclusions: Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption. Impact and implications:: Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption.http://www.sciencedirect.com/science/article/pii/S2589555924002349CDKN1ASteatotic liver disease (SLD)HepatocyteSenescenceMetabolic dysregulationPalbociclib |
| spellingShingle | Arantza Lamas-Paz Alejandro Hionides-Gutiérrez Feifei Guo Gonzalo Jorquera Laura Morán-Blanco Raquel Benedé-Ubieto Mariana Mesquita Olga Estévez-Vázquez Kang Zheng Marina Mazariegos Elena Vázquez-Ogando Elena Blázquez-López Iris Asensio Beste Mutlu Beatriz Gomez-Santos María Isabel Peligros Javier Vaquero Rafael Bañares Teresa C. Delgado María Luz Martínez-Chantar Eduardo Martínez-Naves Carlos Sanz-García Mohamed Ramadan Mohamed Sofía Tesolato Pilar Iniesta Rocío Gallego-Durán Douglas Maya-Miles Javier Ampuero Manuel Romero-Gómez Ana Martínez-Alcocer David Sanfeliu-Redondo Anabel Fernández-Iglesias Jordi Gracia-Sancho Mar Coll Isabel Graupera Pere Ginès Andrea Ciudin Jesús Rivera-Esteban Juan M. Pericàs Matías A. Ávila Maria Dolores Frutos Carlos Manuel Martínez-Cáceres Bruno Ramos-Molina Patricia Aspichueta Pere Puigserver Yulia A. Nevzorova Francisco Javier Cubero Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis JHEP Reports CDKN1A Steatotic liver disease (SLD) Hepatocyte Senescence Metabolic dysregulation Palbociclib |
| title | Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis |
| title_full | Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis |
| title_fullStr | Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis |
| title_full_unstemmed | Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis |
| title_short | Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis |
| title_sort | loss of cdkn1a protects against masld alone or with alcohol intake by preserving lipid homeostasis |
| topic | CDKN1A Steatotic liver disease (SLD) Hepatocyte Senescence Metabolic dysregulation Palbociclib |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924002349 |
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