1. Academic Validation
  2. A long-acting FGF21 attenuates metabolic dysfunction-associated steatohepatitis-related fibrosis by modulating NR4A1-mediated Ly6C phenotypic switch in macrophages

A long-acting FGF21 attenuates metabolic dysfunction-associated steatohepatitis-related fibrosis by modulating NR4A1-mediated Ly6C phenotypic switch in macrophages

  • Br J Pharmacol. 2024 Apr 28. doi: 10.1111/bph.16378.
Yue Ji 1 Yiliang Duan 1 Yuanyuan Li 1 Qingzhou Lu 1 Dingkang Liu 1 Yifan Yang 1 Ruilong Chang 1 Jing Tian 1 Wenbing Yao 1 Jun Yin 1 Xiangdong Gao 1
Affiliations

Affiliation

  • 1 Jiangsu Key Laboratory of Draggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Abstract

Background and purpose: Because of the absence of effective therapies for metabolic dysfunction-associated steatohepatitis (MASH), there is a rising interest in Fibroblast Growth Factor 21 (FGF21) analogues due to their potential anti-fibrotic activities in MASH treatment. PsTag-FGF21, a long-acting FGF21 analogue, has demonstrated promising therapeutic effects in several MASH mouse models. However, its efficacy and mechanism against MASH-related fibrosis remain less well defined, compared with the specific mechanisms through which FGF21 improves glucose and lipid metabolism.

Experimental approach: The effectiveness of PsTag-FGF21 was evaluated in two MASH-fibrosis models. Co-culture systems involving macrophages and hepatic stellate cells (HSCs) were employed for further assessment. Hepatic macrophages were selectively depleted by administering liposome-encapsulated clodronate via tail vein injections. RNA Sequencing and cytokine profiling were conducted to identify key factors involved in macrophage-HSC crosstalk.

Key results: We first demonstrated the significant attenuation of hepatic fibrosis by PsTag-FGF21 in two MASH-fibrosis models. Furthermore, we highlighted the crucial role of macrophage phenotypic switch in PsTag-FGF21-induced HSC deactivation. FGF21 was demonstrated to regulate macrophages in a PsTag-FGF21-like manner. NR4A1, a nuclear factor which is notably down-regulated in human livers with MASH, was identified as a mediator responsible for PsTag-FGF21-induced phenotypic switch. Transcriptional control over insulin-like growth factor 1, a crucial factor in macrophage-HSC crosstalk, was exerted by the intrinsically disordered region domain of NR4A1.

Conclusion and implications: Our results have elucidated the previously unclear mechanisms through which PsTag-FGF21 treats MASH-related fibrosis and identified NR4A1 as a potential therapeutic target for fibrosis.

Keywords

FGF21; Ly6C; MASH; NR4A1; intercellular crosstalk; liver fibrosis; macrophage.

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