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FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis

View ORCID ProfileCong Liu, Milena Schönke, Borah Spoorenberg, Joost M. Lambooij, Hendrik J.P. van der Zande, View ORCID ProfileEnchen Zhou, Maarten E. Tushuizen, View ORCID ProfileAnne-Christine Andréasson, Andrew Park, Stephanie Oldham, Martin Uhrbom, Ingela Ahlstedt, Yasuhiro Ikeda, View ORCID ProfileKristina Wallenius, Xiao-Rong Peng, Bruno Guigas, Mariëtte R. Boon, Yanan Wang, View ORCID ProfilePatrick C.N. Rensen
doi: https://doi.org/10.1101/2022.09.20.508654
Cong Liu
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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  • ORCID record for Cong Liu
Milena Schönke
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Borah Spoorenberg
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Joost M. Lambooij
3Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
4Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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Hendrik J.P. van der Zande
3Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
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Enchen Zhou
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Maarten E. Tushuizen
5Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Anne-Christine Andréasson
6Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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  • ORCID record for Anne-Christine Andréasson
Andrew Park
7Biologics Engineering and Targeted Delivery, Oncology R&D, AstraZeneca, Gaithersburg, USA
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Stephanie Oldham
8Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, USA
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Martin Uhrbom
6Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Ingela Ahlstedt
6Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Yasuhiro Ikeda
7Biologics Engineering and Targeted Delivery, Oncology R&D, AstraZeneca, Gaithersburg, USA
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Kristina Wallenius
6Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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  • ORCID record for Kristina Wallenius
Xiao-Rong Peng
6Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Bruno Guigas
3Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
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Mariëtte R. Boon
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Yanan Wang
9Med-X institute, Center for Immunological and Metabolic Diseases, and Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, China
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  • For correspondence: y_wang@xjtufh.edu.cn p.c.n.rensen@lumc.nl
Patrick C.N. Rensen
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
9Med-X institute, Center for Immunological and Metabolic Diseases, and Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, China
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  • ORCID record for Patrick C.N. Rensen
  • For correspondence: y_wang@xjtufh.edu.cn p.c.n.rensen@lumc.nl
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Abstract

Analogues of the hepatokine FGF21 are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.

Competing Interest Statement

ACA, AP, SO, MU, IA, YI, KW and XRP are employees of AstraZeneca.

Footnotes

  • Grant support: This work was supported by the Dutch Diabetes Research Foundation (2015.81.1808 to M.R.B.); Netherlands Organisation for Scientific Research-NWO (VENI grant 91617027 to Y.W.); Chinese Scholarship Council grants (CSC 201606010321 to E.Z.); the Novo Nordisk Foundation (NNF18OC0032394 to M.S.); and the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON-GENIUS-2 to P.C.N.R.).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 22, 2022.
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FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis
Cong Liu, Milena Schönke, Borah Spoorenberg, Joost M. Lambooij, Hendrik J.P. van der Zande, Enchen Zhou, Maarten E. Tushuizen, Anne-Christine Andréasson, Andrew Park, Stephanie Oldham, Martin Uhrbom, Ingela Ahlstedt, Yasuhiro Ikeda, Kristina Wallenius, Xiao-Rong Peng, Bruno Guigas, Mariëtte R. Boon, Yanan Wang, Patrick C.N. Rensen
bioRxiv 2022.09.20.508654; doi: https://doi.org/10.1101/2022.09.20.508654
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FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis
Cong Liu, Milena Schönke, Borah Spoorenberg, Joost M. Lambooij, Hendrik J.P. van der Zande, Enchen Zhou, Maarten E. Tushuizen, Anne-Christine Andréasson, Andrew Park, Stephanie Oldham, Martin Uhrbom, Ingela Ahlstedt, Yasuhiro Ikeda, Kristina Wallenius, Xiao-Rong Peng, Bruno Guigas, Mariëtte R. Boon, Yanan Wang, Patrick C.N. Rensen
bioRxiv 2022.09.20.508654; doi: https://doi.org/10.1101/2022.09.20.508654

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