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

Autor: Ji Y; 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., Duan Y; 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., Li Y; 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., Lu Q; 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., Liu D; 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., Yang Y; 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., Chang R; 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., Tian J; 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., Yao W; 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., Yin J; 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., Gao X; 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.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Aug; Vol. 181 (16), pp. 2923-2946. Date of Electronic Publication: 2024 Apr 28.
DOI: 10.1111/bph.16378
Abstrakt: 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.
(© 2024 British Pharmacological Society.)
Databáze: MEDLINE
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