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Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
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Hepatocyte-Derived FGF1 Alleviates Isoniazid and Rifampicin-Induced Liver Injury by Regulating HNF4α-Mediated Bile
Qian Lin1, Jiaren Zhang1, Jie Qi1
1School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 28, 2024
Summary
Fibroblast growth factor 1 (FGF1) protects against anti-tuberculosis drug-induced liver injury (ATB-DILI). FGF1 downregulation exacerbates liver injury by disrupting bile acid homeostasis, while FGF1 analogs offer therapeutic potential.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Anti-tuberculosis drug-induced liver injury (ATB-DILI) from isoniazid (INH) and rifampicin (RIF) is a significant health concern with unclear pathophysiology.
- Fibroblast growth factors (FGFs) are implicated in liver pathophysiology.
Purpose of the Study:
- To investigate the role of FGFs in INH and RIF-induced liver injury.
- To elucidate the underlying mechanisms of FGF1 in regulating bile acid homeostasis during ATB-DILI.
Main Methods:
- Systematic screening in mouse models and human patients challenged with INH and RIF.
- Assessment of hepatocyte-specific Fgf1 deficiency and pharmacological administration of FGF1 analog (FGF1ΔHBS).
- Analysis of bile acid synthases, bile acid accumulation, and the FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway.
Main Results:
- Hepatic FGF1 expression was significantly downregulated in INH and RIF-exposed mice and patients.
- Fgf1 deficiency exacerbated liver injury, linked to elevated bile acid synthases and aberrant bile acid accumulation.
- FGF1ΔHBS administration alleviated liver injury by restoring bile acid homeostasis.
- FGF1 repressed Hnf4α transcription via FGFR4-ERK1/2 signaling, reducing bile acid synthase expression.
Conclusions:
- Hepatic FGF1 acts as a negative regulator of bile acid biosynthesis, protecting against INH and RIF-induced liver injury.
- Restoring bile acid homeostasis through FGF1 modulation presents a potential therapeutic strategy for ATB-DILI.
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