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Updated: May 20, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
FGF21 reverses MASH through coordinated actions on the CNS and liver
Jesse P Rose1, Donald A Morgan1, Andrew I Sullivan1
1Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Fibroblast growth factor 21 (FGF21) reverses metabolic dysfunction-associated steatohepatitis (MASH) by distinct pathways. FGF21 targets the CNS for triglyceride reduction and liver cells for cholesterol reduction, offering new MASH treatment strategies.
Area of Science:
- Hepatology
- Endocrinology
- Neuroscience
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasing health concerns with few treatments.
- Fibroblast growth factor 21 (FGF21) analogs show promise for MASH, but their mechanisms are unclear.
Purpose of the Study:
- To elucidate the distinct mechanisms by which FGF21 ameliorates MASH.
- To identify the specific cellular targets and pathways through which FGF21 exerts its metabolic benefits.
Main Methods:
- Investigated FGF21's effects on hepatic triglyceride and cholesterol levels in mouse models.
- Utilized targeted signaling studies to differentiate FGF21's actions on the central nervous system (CNS) and hepatocytes.
- Examined the role of CNS-mediated sympathetic nerve activity in FGF21's metabolic effects.
Main Results:
- FGF21 signaling to CNS glutamatergic neurons reduces hepatic triglycerides and fibrosis.
- FGF21 signaling directly to hepatocytes is essential for lowering hepatic cholesterol.
- FGF21 in the CNS enhances sympathetic liver innervation, suppressing de novo lipogenesis.
Conclusions:
- FGF21 employs separate mechanisms to lower hepatic fat and cholesterol in MASH.
- Targeting FGF21 pathways in the CNS and liver offers a dual approach for MASH therapy.
- Understanding these mechanisms provides critical insights for developing novel MASH pharmacological treatments.
