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Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD)

内分泌学 内科学 FGF19型 肝硬化 脂肪组织 FGF21型 脂肪变性 脂肪肝 脂肪性肝炎 肝病 下调和上调 生物 医学 成纤维细胞生长因子 疾病 生物化学 受体 基因
作者
Amaya López-Pascual,Joan Salvador Russo-Cabrera,Nuria Ardaiz,Tiffany Palmer,Anne-Renee Graham,Iker Uriarte,Celia Gomar,David Ruiz-Guillamon,María U. Latasa,María Arechederra,Antonio Fontanellas,María J. Monte,José J.G. Marı́n,Carmen Berasain,Carlos del Río,Maite G. Fernández‐Barrena,Paolo G.V. Martini,Joshua R. Schultz,Pedro Berraondo,Matías A. Ávila
出处
期刊:Clinical Science [Portland Press]
被引量:4
标识
DOI:10.1042/cs20241137
摘要

Metabolic dysfunction-associated steatohepatitis (MASH), represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BA) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the downregulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.
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