Reversal of metabolic dysfunction associated steatohepatitis by fibroblast growth factor 21

Metabolic dysfunction-associated steatotic liver disease (MASLD) develops as a result of dysregulation of lipid metabolism leading to excess lipid deposition in the liver. Left untreated, toxic lipid species accumulate in the liver promoting the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) with hepatocyte damage, inflammation, and fibrosis. MASLD and 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, whereas FGF21 action directly on hepatocytes is necessary and sufficient for FGF21-mediated reduction in hepatic cholesterol levels. Our data indicate that the effects of FGF21-mediated reduction of triglycerides and cholesterol are additive to resolve fibrosis in MASH. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver which suppresses hepatic de novo lipogenesis to lower hepatic triglycerides. These results provide critical insights into a promising pharmacological target to treat MASH.