FGF21 Hormone Can Reverse Fatty Liver Disease
The disease affects an estimated 38% of the global population.
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A new study published in Cell Metabolism reveals how the hormone fibroblast growth factor 21 (FGF21) can reverse fatty liver disease in mice by primarily signaling the brain to improve liver metabolism.
Fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by an accumulation of fat in the liver. It can progress to metabolic dysfunction-associated steatohepatitis (MASH), which involves liver inflammation and fibrosis, potentially leading to cirrhosis. MASLD affects an estimated 38% of the global population, and there is currently only one FDA-approved treatment for MASH.
The study – led by Matthew Potthoff, PhD, professor of biochemistry and physiology at the University of Oklahoma College of Medicine and deputy director of OU Health Harold Hamm Diabetes Center – provides new insight into how FGF21 acts to reverse disease progression. Drugs targeting FGF21 signaling are currently undergoing phase 3 clinical trials.
The researchers found that FGF21 activates a signaling pathway in the brain that triggers changes in nerve activity directed to the liver. This feedback loop reduces liver fat accumulation and reverses fibrosis. In addition to its effect via the brain, FGF21 also directly signals the liver to lower cholesterol levels.
Unlike many treatments that target the liver directly, the majority of FGF21’s therapeutic effects arise from its action on the brain, which then modulates liver metabolism. The dual signaling mechanism effectively regulates different types of lipids within the liver.
FGF21 shares similarities with glucagon-like peptide 1 (GLP-1), a hormone family used in weight loss drugs. Both hormones originate in peripheral tissues – FGF21 from the liver and GLP-1 from the intestine – and exert effects by signaling to the brain to regulate metabolism.
Importantly, the study showed that FGF21 reversed liver fibrosis, the pathological component of MASH, even while mice continued consuming a diet that induces the disease. These findings clarify the hormone’s mechanism of action and may inform development of more targeted therapies in the future.
Reference: Potthoff M, Rose J, Morgan D, et al. FGF21 reverses MASH through coordinated actions on the CNS and liver. Cell Metab. 2025. doi:10.1016/j.cmet.2025.04.014
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