Researchers at the Medical University of South Carolina (MUSC) have found evidence that the asthma medication formoterol may reverse metabolic dysfunction-associated steatohepatitis (MASH), a progressive fatty liver disease associated with obesity and type 2 diabetes that can lead to fibrosis, cirrhosis, liver failure, and liver transplantation. The research, published in npj Metabolic Health and Disease, arose unexpectedly as a result of findings on the use of formoterol in mouse models of diabetic kidney injury, which also showed that the mice had low levels of liver fat accumulation.
“Kind of unexpectedly, we found that the liver damage also reversed,” said senior author Joshua Lipschutz, MD, division director of nephrology and Arthur Williams Endowed Chair in nephrology at MUSC.
Based on this observation, the MUSC researchers initiated a study to find out whether the beta-2 adrenergic receptor pathway targeted by formoterol could influence metabolic disease in the liver as well as the kidney. According to the researchers, the connection between the diseases lies in shared metabolic dysfunction associated with type 2 diabetes relating to mitochondrial dysfunction and impaired energy metabolism.
To test the hypothesis, the team used a high-fat diet mouse model designed to mimic MASH. Mice fed the diet for 16 weeks developed liver steatosis and were subsequently treated with formoterol for four weeks. Testing of the mice after the four weeks of treatment found that steatosis was largely resolved as a result.
The evidence showed that formoterol increased mitochondrial biogenesis, a process that increases the number and function of mitochondria within cells.
“It looked like formoterol was rescuing the injury by increasing mitochondrial biogenesis,” Lischutz said. “It kind of revs up the mitochondria so they work better.”
The researcher noted that mice treated with formoterol had increased levels of PGC1α (a protein that helps control how cells produce and use energy) and electron transport chain proteins, along with an increase in mitochondrial proteins and lower lipid accumulation in liver tissue. Human HepaRG liver cells exposed to free fatty acids also showed reduced lipid accumulation and increased after formoterol treatment.
“The coordinated induction of oxidative phosphorylation and amino acid metabolism pathways suggests that formoterol may promote metabolic competence through non-lipid sources, including amino acids,” the researchers wrote.
While there were no approved drugs to treat MASH when the MUSC researchers initiated their study, current treatments still remain limited with resmetirom and semaglutide the only current approved therapies for this condition. Both medications have shown only limited efficacy in a subset of patients and have known side effects.
“All the current drugs for diabetic nephropathy only slow progression, but they don’t reverse the damage. This drug actually reversed the damage at the histologic, ultrastructural, and functional levels,” said Lipschutz.
Further, formoterol is already an approved and established medication that has been prescribed for year to treat both asthma and chronic obstructive pulmonary disease (COPD). Because its metabolic effects in humans and its safety profile has been detailed in its approval for these conditions, it could hasten approval for these other therapeutic uses.
“If you can repurpose something that’s approved and already being used safely, that’s kind of our dream as physician-scientists,” Lipschutz added.
Lipschutz and colleagues are currently conducting a clinical trial for the use of formoterol in chronic kidney disease (NCT07022418). Future research will focus on what dosing levels would be appropriate to use as treatment for CKD and MASH, whether inhaled delivery would be effective, and how durable the response to this potential treatment could be.
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