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

  1. Cong Liu
  2. Milena Schönke
  3. Borah Spoorenberg
  4. Joost M Lambooij
  5. Hendrik JP van der Zande
  6. Enchen Zhou
  7. Maarten E Tushuizen
  8. Anne-Christine Andreasson
  9. Andrew Park
  10. Stephanie Oldham
  11. Martin Uhrbom
  12. Ingela Ahlstedt
  13. Yasuhiro Ikeda
  14. Kristina Wallenius
  15. Xiao-Rong Peng
  16. Bruno Guigas
  17. Mariëtte R Boon  Is a corresponding author
  18. Yanan Wang  Is a corresponding author
  19. Patrick CN Rensen  Is a corresponding author
  1. Leiden University Medical Center, Netherlands
  2. AstraZeneca, Sweden
  3. AstraZeneca, United States
  4. First Affiliated Hospital of Xi'an Jiaotong University, China

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Cong Liu

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2852-8953
  2. Milena Schönke

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  3. Borah Spoorenberg

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  4. Joost M Lambooij

    Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  5. Hendrik JP van der Zande

    Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  6. Enchen Zhou

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3739-4934
  7. Maarten E Tushuizen

    5Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  8. Anne-Christine Andreasson

    Research and Early Development, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Anne-Christine Andreasson, employee of AstraZeneca.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8323-0658
  9. Andrew Park

    Biologics Engineering and Targeted Delivery, AstraZeneca, Gaithersburg, United States
    Competing interests
    Andrew Park, employee of AstraZeneca.
  10. Stephanie Oldham

    Research and Early Development, AstraZeneca, Gaithersburg, United States
    Competing interests
    Stephanie Oldham, employee of AstraZeneca.
  11. Martin Uhrbom

    Research and Early Development, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Martin Uhrbom, employee of AstraZeneca.
  12. Ingela Ahlstedt

    Research and Early Development, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Ingela Ahlstedt, employee of AstraZeneca.
  13. Yasuhiro Ikeda

    Biologics Engineering and Targeted Delivery, AstraZeneca, Gaithersburg, United States
    Competing interests
    Yasuhiro Ikeda, employee of AstraZeneca.
  14. Kristina Wallenius

    Research and Early Development, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Kristina Wallenius, employee of AstraZeneca.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3231-2733
  15. Xiao-Rong Peng

    Research and Early Development, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Xiao-Rong Peng, employee of AstraZeneca.
  16. Bruno Guigas

    Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  17. Mariëtte R Boon

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    For correspondence
    m.r.boon@lumc.nl
    Competing interests
    No competing interests declared.
  18. Yanan Wang

    Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
    For correspondence
    y_wang@xjtufh.edu.cn
    Competing interests
    No competing interests declared.
  19. Patrick CN Rensen

    Department of Medicine, Leiden University Medical Center, Leiden, Netherlands
    For correspondence
    p.c.n.rensen@lumc.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8455-4988

Funding

Diabetes Fonds (2015.81.1808)

  • Mariëtte R Boon

The Netherlands Organisation for Scientific Research-NWO (VENI grant 91617027)

  • Yanan Wang

Chinese Scholarship Council grant (CSC 201606010321)

  • Enchen Zhou

The Novo Nordisk Foundation (NNF18OC0032394)

  • Milena Schönke

The Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON-GENIUS-2)

  • Patrick CN Rensen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were carried out according to the Institute for Laboratory Animal Research Guide for the Care and Use of Laboratory Animals, and were approved by the National Committee for Animal Experiments (Protocol No. AVD1160020173305) and by the Ethics Committee on Animal Care and Experimentation of the Leiden University Medical Center (Protocol No. PE.18.034.041).

Reviewing Editor

  1. Pramod Mistry, Yale School of Medicine, United States

Publication history

  1. Received: August 30, 2022
  2. Accepted: January 16, 2023
  3. Accepted Manuscript published: January 17, 2023 (version 1)

Copyright

© 2023, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cong Liu
  2. Milena Schönke
  3. Borah Spoorenberg
  4. Joost M Lambooij
  5. Hendrik JP van der Zande
  6. Enchen Zhou
  7. Maarten E Tushuizen
  8. Anne-Christine Andreasson
  9. Andrew Park
  10. Stephanie Oldham
  11. Martin Uhrbom
  12. Ingela Ahlstedt
  13. Yasuhiro Ikeda
  14. Kristina Wallenius
  15. Xiao-Rong Peng
  16. Bruno Guigas
  17. Mariëtte R Boon
  18. Yanan Wang
  19. Patrick CN Rensen
(2023)
FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis
eLife 12:e83075.
https://doi.org/10.7554/eLife.83075

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