Journal article
FGF21 reverses MASH through coordinated actions on the CNS and liver
Cell metabolism, Vol.37(7), pp.1515-1529.e6
07/2025
DOI: 10.1016/j.cmet.2025.04.014
PMCID: PMC12409791
PMID: 40367940
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.
Details
- Title: Subtitle
- FGF21 reverses MASH through coordinated actions on the CNS and liver
- Creators
- Jesse P Rose - University of IowaDonald A Morgan - University of IowaAndrew I Sullivan - University of IowaXiaorong Fu - The University of Texas Southwestern Medical CenterMelissa Inigo-Vollmer - The University of Texas Southwestern Medical CenterShawn C Burgess - The University of Texas Southwestern Medical CenterDavid K Meyerholz - University of IowaKamal Rahmouni - University of IowaMatthew J Potthoff - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.37(7), pp.1515-1529.e6
- DOI
- 10.1016/j.cmet.2025.04.014
- PMID
- 40367940
- PMCID
- PMC12409791
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- CELL PRESS
- Grant note
- National Institutes of Health (NIH): R01DK106104, R01AA027654, R01HL162773, P30DK54759 Veterans Affairs Merit Review Program: I01BX004634, IK6BX006040 Cystic Fibrosis Foundation Research & Development ProgramUniversity of Iowa Carver College of Medicine
We thank Dr. Birgitte Andersen (Novo Nordisk) for providing the FGF21 protein and Dr. Jia Pan (Novo Nordisk) for providing peptide-19. This work was funded by the National Institutes of Health (NIH) R01DK106104 (M.J.P.) , R01AA027654 (M.J.P.) , R01HL162773 (K.R.) , and P30DK54759 (D.K.M.-Core Director) ; the Veterans Affairs Merit Review Program I01BX004634 (M.J.P.) and IK6BX006040 (K.R.) ; the Cystic Fibrosis Foundation Research & Development Program (D.K.M.-Core Director) ; and the University of Iowa Carver College of Medicine (M.J.P.) . The authors would like to acknowledge the University of Iowa Central Microscopy Research Facility and Genome Editing Facility, the Genomics Division of the Iowa Institute of Human Genetics, and the Iowa Comparative Pathology Laboratory.
- Language
- English
- Electronic publication date
- 05/08/2025
- Date published
- 07/2025
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984823075902771
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