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Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis

(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibrobla...

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Autores principales: Puengel, Tobias, Lefere, Sander, Hundertmark, Jana, Kohlhepp, Marlene, Penners, Christian, Van de Velde, Frederique, Lapauw, Bruno, Hoorens, Anne, Devisscher, Lindsey, Geerts, Anja, Boehm, Stephanie, Zhao, Qihong, Krupinski, John, Charles, Edgar D., Zinker, Bradley, Tacke, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224277/
https://www.ncbi.nlm.nih.gov/pubmed/35743140
http://dx.doi.org/10.3390/ijms23126696
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author Puengel, Tobias
Lefere, Sander
Hundertmark, Jana
Kohlhepp, Marlene
Penners, Christian
Van de Velde, Frederique
Lapauw, Bruno
Hoorens, Anne
Devisscher, Lindsey
Geerts, Anja
Boehm, Stephanie
Zhao, Qihong
Krupinski, John
Charles, Edgar D.
Zinker, Bradley
Tacke, Frank
author_facet Puengel, Tobias
Lefere, Sander
Hundertmark, Jana
Kohlhepp, Marlene
Penners, Christian
Van de Velde, Frederique
Lapauw, Bruno
Hoorens, Anne
Devisscher, Lindsey
Geerts, Anja
Boehm, Stephanie
Zhao, Qihong
Krupinski, John
Charles, Edgar D.
Zinker, Bradley
Tacke, Frank
author_sort Puengel, Tobias
collection PubMed
description (1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients.
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spelling pubmed-92242772022-06-24 Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis Puengel, Tobias Lefere, Sander Hundertmark, Jana Kohlhepp, Marlene Penners, Christian Van de Velde, Frederique Lapauw, Bruno Hoorens, Anne Devisscher, Lindsey Geerts, Anja Boehm, Stephanie Zhao, Qihong Krupinski, John Charles, Edgar D. Zinker, Bradley Tacke, Frank Int J Mol Sci Article (1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients. MDPI 2022-06-15 /pmc/articles/PMC9224277/ /pubmed/35743140 http://dx.doi.org/10.3390/ijms23126696 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Puengel, Tobias
Lefere, Sander
Hundertmark, Jana
Kohlhepp, Marlene
Penners, Christian
Van de Velde, Frederique
Lapauw, Bruno
Hoorens, Anne
Devisscher, Lindsey
Geerts, Anja
Boehm, Stephanie
Zhao, Qihong
Krupinski, John
Charles, Edgar D.
Zinker, Bradley
Tacke, Frank
Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title_full Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title_fullStr Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title_full_unstemmed Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title_short Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
title_sort combined therapy with a ccr2/ccr5 antagonist and fgf21 analogue synergizes in ameliorating steatohepatitis and fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224277/
https://www.ncbi.nlm.nih.gov/pubmed/35743140
http://dx.doi.org/10.3390/ijms23126696
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