Therapeutic targeting of adipose tissue macrophages ameliorates liver fibrosis in non-alcoholic fatty liver disease.

Autor:	Martínez-Sánchez C; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Bassegoda O; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Deng H; Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Almodóvar X; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Ibarzabal A; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, Barcelona, Spain.; Gastrointestinal Surgery Department, Hospital Clínic de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain., de Hollanda A; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain., Martínez García de la Torre RA; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Blaya D; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Ariño S; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Jiménez-Esquivel N; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Aguilar-Bravo B; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Vallverdú J; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Montironi C; Molecular Biology Core & Pathology Department, Hospital Clínic of Barcelona, Spain., Osorio-Conles O; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain., Fundora Y; Department of General and Digestive Surgery, Hospital Clinic de Barcelona, Barcelona, Spain., Sánchez Moreno FJ; Department of General and Digestive Surgery, Hospital Clinic de Barcelona, Barcelona, Spain., Gómez-Valadés AG; Neuronal Control of Metabolism (NeuCoMe) Laboratory, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Aguilar-Corominas L; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Soria A; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Pose E; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Juanola A; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Cervera M; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Perez M; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Hernández-Gea V; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Affò S; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain., Swanson KS; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Ferrer-Fàbrega J; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Barcelona Clínic Liver Cancer Group (BCLC), IDIBAPS, Barcelona, Spain.; Hepatic Oncology Unit, Hospital Clínic, Barcelona, Spain.; Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Institute Clínic of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, Barcelona, Spain.; Department of Medicine, University of Barcelona, Barcelona, Spain., Balibrea JM; Endocrine, Metabolic & Bariatric Surgery Unit, Germans Trias i Pujol Hospital, Autonomous University of Barcelona, Barcelona, Spain., Sancho-Bru P; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Vidal J; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain., Ginès P; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.; Department of General and Digestive Surgery, Hospital Clinic de Barcelona, Barcelona, Spain., Smith AM; Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.; Carle Illinois College of Medicine, Urbana, IL, USA.; Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Graupera I; Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit, Hospital Clínic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Coll M; Department of Medicine, University of Barcelona, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Jun 27; Vol. 5 (10), pp. 100830. Date of Electronic Publication: 2023 Jun 27 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2023.100830
Abstrakt:	Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model. Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed. Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro , the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids. Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD. Impact and Implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD. Competing Interests: All authors declare no conflicts of interest related to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Authors.)
Databáze:	MEDLINE
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