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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic
Amaya Lopez-Pascual1,2, Joan S Russo-Cabrera3, Nuria Ardaiz3
1Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
Abstract:
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 (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation 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.
Insights
Non-mitogenic FGF19 mRNA therapy reversed metabolic dysfunction-associated steatohepatitis (MASH) in mice. This treatment reduced liver fat, improved metabolic health, and modulated bile acids, showing promise for MASH treatment.
Area of Science:
- Hepatology and Metabolic Diseases
- Molecular Therapeutics
- Biotechnology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern.
- MASH progression can lead to severe liver conditions like cirrhosis and hepatocellular carcinoma.
- Fibroblast growth factor (FGF)-19 is a key metabolic regulator with therapeutic potential for MASH.
Purpose of the Study:
- To evaluate the therapeutic efficacy of non-mitogenic (NM)-FGF19 mRNA encapsulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) for MASH.
- To assess the impact of NM-FGF19-mRNAs-LNPs on metabolic parameters and liver histology in a diet-induced MASH mouse model.
Main Methods:
- Diet-induced obesity and MASH (DIO-MASH) model established in C57BL/6NTac male mice.
- Weekly intravenous administration of NM-FGF19-mRNAs-LNPs or control mRNA-LNPs for six weeks.
- Comprehensive analysis including body weight, adipose tissue, serum markers, liver histology, insulin sensitivity, and transcriptomics.
Main Results:
- NM-FGF19-mRNAs-LNPs treatment significantly reduced body weight, adipose tissue, and serum transaminases in DIO-MASH mice.
- Histological analysis confirmed MASH feature reversal, including reduced steatosis without fibrosis exacerbation.
- Treatment modulated hepatic bile acid composition, improved cholesterol homeostasis, and down-regulated metabolic dysfunction genes in adipose tissue.
Conclusions:
- NM-FGF19-mRNA-LNPs demonstrate significant therapeutic potential for MASH by addressing hepatic and systemic metabolic dysregulation.
- The therapy effectively reduces liver steatosis, enhances metabolic parameters, and influences bile acid metabolism, suggesting mechanistic relevance.
- This study highlights the translational promise of mRNA-based therapies for managing the complex nature of MASH and associated metabolic disorders.
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