Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis

  • JHEP Rep. 2024 Oct 5;7(1):101230. doi: 10.1016/j.jhepr.2024.101230.
Arantza Lamas-Paz  1  2 ,  Alejandro Hionides-Gutiérrez  1 ,  Feifei Guo  1  3 ,  Gonzalo Jorquera  4  5 ,  Laura Morán-Blanco  1 ,  Raquel Benedé-Ubieto  1 ,  Mariana Mesquita  1  6 ,  Olga Estévez-Vázquez  1 ,  Kang Zheng  1  7 ,  Marina Mazariegos  1 ,  Elena Vázquez-Ogando  8  9  10 ,  Elena Blázquez-López  8  9  10 ,  Iris Asensio  8  9  10 ,  Beste Mutlu  11  12 ,  Beatriz Gomez-Santos  13  14 ,  María Isabel Peligros  15 ,  Javier Vaquero  8  9  10 ,  Rafael Bañares  8  9  10 ,  Teresa C Delgado  16 ,  María Luz Martínez-Chantar  10  16 ,  Eduardo Martínez-Naves  1  2 ,  Carlos Sanz-García  1 ,  Mohamed Ramadan Mohamed  17 ,  Sofía Tesolato  18  19 ,  Pilar Iniesta  18  19 ,  Rocío Gallego-Durán  10  20 ,  Douglas Maya-Miles  10  20 ,  Javier Ampuero  10  20 ,  Manuel Romero-Gómez  10  20 ,  Ana Martínez-Alcocer  10  21 ,  David Sanfeliu-Redondo  10  21 ,  Anabel Fernández-Iglesias  10  21 ,  Jordi Gracia-Sancho  10  21  22 ,  Mar Coll  10  23 ,  Isabel Graupera  10  23  24 ,  Pere Ginès  10  23  24 ,  Andrea Ciudin  25  26 ,  Jesús Rivera-Esteban  27  28 ,  Juan M Pericàs  10  27 ,  Matías A Ávila  10  29  30 ,  Maria Dolores Frutos  31 ,  Carlos Manuel Martínez-Cáceres  32 ,  Bruno Ramos-Molina  33 ,  Patricia Aspichueta  10  13  14 ,  Pere Puigserver  11  12 ,  Yulia A Nevzorova  1  9  10 ,  Francisco Javier Cubero  1  9  10
Affiliations
  • 1. Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain.
  • 2. 12 de Octubre Health Research Institute (imas12), Madrid, Spain.
  • 3. Department of Obstetrics and Gynaecology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 4. Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile.
  • 5. Physiology Institute, Science Faculty, Universidad de Valparaíso, Valparaíso, Chile.
  • 6. State University of Campinas, Campinas, Sao Paulo, Brazil.
  • 7. Department of Anesthesiology, Nanjing Pukou District Hospital of Chinese Medicine Central Laboratory Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
  • 8. Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
  • 9. Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain.
  • 10. Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain.
  • 11. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 12. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 13. Department of Physiology, Basque Country University (UPV/EHU) School of Medicine and Nursing, Bilbao, Spain.
  • 14. Biobizkaia Health Institute, Barakaldo, Spain.
  • 15. Servicio de Anatomía Patológica Hospital General Universitario Gregorio Marañón Madrid, Spain.
  • 16. Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain.
  • 17. Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
  • 18. Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain.
  • 19. San Carlos Health Research Institute (IdISSC), Madrid, Spain.
  • 20. Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
  • 21. Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain.
  • 22. Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 23. Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 24. Liver Unit, Hospital Clinic, Barcelona, Spain.
  • 25. Endocrinology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain.
  • 26. Centre for Biomedical Research, Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
  • 27. Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain.
  • 28. Puerta de Hierro University Hospital, Instituto de Investigación Sanitaria Puerta de Hierro, Majadahonda, Madrid, Spain.
  • 29. Hepatology Laboratory, Solid Tumors Program, CIMA, University of Navarra, Pamplona, Spain.
  • 30. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
  • 31. Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain.
  • 32. Experimental Pathology Service, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
  • 33. Laboratorio de Obesidad y Metabolismo, Instituto de Investigación Biomédica de Murcia (IMIB-Arrixaca), Murcia, Spain.
PMID: 39659733 DOI: 10.1016/j.jhepr.2024.101230
Abstract

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.

Keywords
CDKN1A; Hepatocyte; Metabolic dysregulation; Palbociclib; Senescence; Steatotic liver disease (SLD).
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