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. 2025 Jul 1;37(7):1515-1529.e6.
doi: 10.1016/j.cmet.2025.04.014. Epub 2025 May 13.

FGF21 reverses MASH through coordinated actions on the CNS and liver

Jesse P Rose  1 , Donald A Morgan  1 , Andrew I Sullivan  1 , Xiaorong Fu  2 , Melissa Inigo-Vollmer  2 , Shawn C Burgess  2 , David K Meyerholz  3 , Kamal Rahmouni  4 , Matthew J Potthoff  5
Affiliations

FGF21 reverses MASH through coordinated actions on the CNS and liver

Jesse P Rose et al. Cell Metab. .

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.

Keywords: FGF21; MASH; MASLD; betaklotho; brain; hepatic innervation; hepatokine; liver; sympathetic nerve activity.

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Conflict of interest statement

Declaration of interests Recombinant human FGF21 protein was provided by Novo Nordisk. Novo Nordisk was not involved with the conceptualization, design, data collection, analysis, or preparation of the manuscript.

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