Beta 2 adrenergic receptor agonists as a treatment for metabolic dysfunction-associated steatohepatitis (MASH)

Abstract

MASH is a leading cause of liver transplantation. Here, we investigated formoterol, a long-acting β2 adrenergic receptor agonist (LABA), in MASH. Mice treated with a high-fat diet (HFD) for sixteen weeks developed liver steatosis and were treated with formoterol or vehicle for four weeks. Steatosis largely resolved following formoterol treatment. To investigate mechanism, we evaluated mitochondrial biogenesis and found in HFD mice treated with formoterol versus vehicle that: PGC1α levels and electron transport chain components were significantly higher; mitochondrial number was increased; and lipids were decreased. Human HepaRG liver cells were then exposed to free fatty acids and/or formoterol. Formoterol attenuated lipid accumulation and increased ATP-linked basal and maximal respiration. Finally, a retrospective analysis of 59,644 patients with MASH showed that patients taking LABAs had fewer complications of advanced liver disease and lower mortality. Together, these data raise the possibility that LABAs, especially formoterol, could be a novel MASH treatment.