2. Academic Validation
  3. Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis

Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis

  • Cell Metab. 2026 Apr 7;38(4):729-745.e9. doi: 10.1016/j.cmet.2026.01.016.
Eva Novoa 1,  Tamara Parracho 2,  Julica Inderhees 3,  Amaia Rodriguez 4,  Cristina Riobello 5,  Jose Iglesias-Moure 2,  Anabel Fernández-Iglesias 6,  Sara Martinez-Martinez 2,  Ana Senra 2,  Samuel Seoane 2,  Marcos Fondevila 1,  Cristina Iglesias 2,  Alba Cabaleiro 2,  Natalia da Silva Lima 2,  Valentina Dorta 2,  Borja López-Picallo 2,  Lucia Ramos-Lage 5,  Ashwin Woodhoo 5,  Miguel Fidalgo 2,  Maria L Martínez-Chantar 7,  Francisco Javier Cubero 8,  Miguel López 1,  Carlos Dieguez 1,  Diana Guallar 5,  Vincent Prevot 9,  Robert F Schwabe 10,  Gema Frühbeck 4,  Javier Crespo 11,  Marta Varela-Rey 5,  Maria J Gonzalez-Rellan 2,  Jordi Gracia-Sancho 6,  Paula Iruzubieta 10,  Markus Schwaninger 12,  Ruben Nogueiras 13
Affiliations

Affiliations

  • 1 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain.
  • 2 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 3 University of Lübeck, Bioanalytic Core Facility, Center for Brain Behaviour and Metabolism, 23562 Lübeck, Germany; University of Lübeck, Institute for Experimental and Clinical Pharmacology and Toxicology, 23562 Lübeck, Germany.
  • 4 CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain; Metabolic Research Laboratory, Clínica Universidad de Navarra and IdiSNA, Pamplona, Spain.
  • 5 Department of Biochemistry and Molecular Biology, CIMUS, IDIS, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 6 Liver Vascular Biology Lab, IDIBAPS - Hospital Clínic de Barcelona - CIBEREHD, 08036 Barcelona, Spain.
  • 7 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, 48160 Bizkaia, Spain; CIBER Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 8 Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; Institute for Research in Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain; CIBER Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 9 Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, European Genomic Institute for Diabetes (EGID), 59000 Lille, France.
  • 10 Department of Medicine, Columbia University, New York, NY 10027, USA.
  • 11 Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39008 Santander, Spain.
  • 12 University of Lübeck, Bioanalytic Core Facility, Center for Brain Behaviour and Metabolism, 23562 Lübeck, Germany.
  • 13 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain; Galicia Agency of Innovation (GAIN), Xunta de Galicia, 15702 Santiago de Compostela, Spain. Electronic address: [email protected].
PMID: 41734768 DOI: 10.1016/j.cmet.2026.01.016
Abstract

Phosphoenolpyruvate carboxykinase 1 (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic Animals and people with fibrosis, correlating negatively with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1 (TGF-β1)-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid (TCA) cycle activity, but PCK1 overexpression reduces acetyl-coenzyme A (CoA), limiting TCA cycle intermediates and ameliorating HSC activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.

Keywords

PCK1; glycolysis; hepatic stellate cells; liver fibrosis; metabolism.

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