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Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆.
J Hepatol. 2020 Apr 29 [Online ahead of print]JH

Abstract

BACKGROUND & AIMS

Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology.

METHODS

Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD.

RESULTS

Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion.

CONCLUSION

Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists.

LAY SUMMARY

Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium; Department of Medicine III, University Hospital Aachen, Aachen, Germany.Department of Medicine III, University Hospital Aachen, Aachen, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.Department of Medicine III, University Hospital Aachen, Aachen, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.Department of Medicine III, University Hospital Aachen, Aachen, Germany.Department of Medicine III, University Hospital Aachen, Aachen, Germany.Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.Department of Medicine III, University Hospital Aachen, Aachen, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.Inventiva, Daix, France.Inventiva, Daix, France.Inventiva, Daix, France.Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium.Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.Inventiva, Daix, France.Department of Medicine III, University Hospital Aachen, Aachen, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany. Electronic address: frank.tacke@charite.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32360434

Citation

Lefere, Sander, et al. "Differential Effects of Selective- and pan-PPAR Agonists On Experimental Steatohepatitis and Hepatic Macrophages☆." Journal of Hepatology, 2020.
Lefere S, Puengel T, Hundertmark J, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. J Hepatol. 2020.
Lefere, S., Puengel, T., Hundertmark, J., Penners, C., Frank, A. K., Guillot, A., de Muynck, K., Heymann, F., Adarbes, V., Defrêne, E., Estivalet, C., Geerts, A., Devisscher, L., Wettstein, G., & Tacke, F. (2020). Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2020.04.025
Lefere S, et al. Differential Effects of Selective- and pan-PPAR Agonists On Experimental Steatohepatitis and Hepatic Macrophages☆. J Hepatol. 2020 Apr 29; PubMed PMID: 32360434.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. AU - Lefere,Sander, AU - Puengel,Tobias, AU - Hundertmark,Jana, AU - Penners,Christian, AU - Frank,Anna Katharina, AU - Guillot,Adrien, AU - de Muynck,Kevin, AU - Heymann,Felix, AU - Adarbes,Vanessa, AU - Defrêne,Evelyne, AU - Estivalet,Céline, AU - Geerts,Anja, AU - Devisscher,Lindsey, AU - Wettstein,Guillaume, AU - Tacke,Frank, Y1 - 2020/04/29/ PY - 2019/09/11/received PY - 2020/03/30/revised PY - 2020/04/13/accepted PY - 2020/5/4/pubmed PY - 2020/5/4/medline PY - 2020/5/4/entrez KW - Biochip KW - Fibrosis KW - Lanifibranor KW - NAFLD KW - Therapy JF - Journal of hepatology JO - J. Hepatol. N2 - BACKGROUND & AIMS: Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology. METHODS: Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD. RESULTS: Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion. CONCLUSION: Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists. LAY SUMMARY: Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/32360434/Differential_effects_of_selective-_and_pan-PPAR_agonists_on_experimental_steatohepatitis_and_hepatic_macrophages L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(20)30269-5 DB - PRIME DP - Unbound Medicine ER -
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