title: p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.
abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Bárbara
authors: B
authors: González-Terán
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Nuria
authors: N
authors: Matesanz
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Ivana
authors: I
authors: Nikolic
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors: María Angeles
authors: MA
authors: Verdugo
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Vinatha
authors: V
authors: Sreeramkumar
authors: Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain Department of Surgery, University of Salamanca, Salamanca, Spain.
authors: Lourdes
authors: L
authors: Hernández-Cosido
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Alfonso
authors: A
authors: Mora
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Georgiana
authors: G
authors: Crainiciuc
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: María Laura
authors: ML
authors: Sáiz
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Edgar
authors: E
authors: Bernardo
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Luis
authors: L
authors: Leiva-Vega
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Elena
authors: E
authors: Rodríguez
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Victor
authors: V
authors: Bondía
authors: Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Salamanca, Spain Department of Medicine, University of Salamanca, Salamanca, Spain.
authors: Jorge L
authors: JL
authors: Torres
authors: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors: Sonia
authors: S
authors: Perez-Sieira
authors: Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain Department of Surgery, University of Salamanca, Salamanca, Spain.
authors: Luis
authors: L
authors: Ortega
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors: Ana
authors: A
authors: Cuenda
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Francisco
authors: F
authors: Sanchez-Madrid
authors: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors: Rubén
authors: R
authors: Nogueiras
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors: Andrés
authors: A
authors: Hidalgo
authors: Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Salamanca, Spain Department of Medicine, University of Salamanca, Salamanca, Spain.
authors: Miguel
authors: M
authors: Marcos
authors: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain guadalupe.sabio@cnic.es.
authors: Guadalupe
authors: G
authors: Sabio
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D018149:Glucose Intolerance; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020556:Neutrophil Infiltration; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology / Q000378:metabolism*; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014280:Triglycerides; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13
keywords: diabetes; inflammation; obesity; steatosis; stress kinases