BACKGROUND: Metabolic dysfunction-associated steatotic liver disease is a prevalent disease that affects nearly one-third of the global population. Recent genome-wide association studies revealed that a common missense variant in the gene encoding mitochondrial amidoxime reducing component 1 (mARC1) is associated with protection from metabolic dysfunction-associated steatotic liver disease, all-cause cirrhosis, and liver-related mortality suggesting a role for mARC1 in liver pathophysiology
however, little is known about its function in the liver. In this study, we aimed to evaluate the impact of mARC1 hepatoprotective variants on protein function, the effect of loss of mARC1 on cellular lipotoxic stress response, and the effect of global or hepatocyte-specific loss of mARC1 in various mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis. METHODS AND RESULTS: Expression and characterization of mARC1 hepatoprotective variants in cells and mouse liver revealed that the mARC1 p.A165T exhibited lower protein levels but maintained its mitochondrial localization. In cells, the knockdown of mARC1 improved cellular bioenergetics and decreased mitochondrial superoxide production in response to lipotoxic stress. Global genetic deletion and hepatocyte-specific knockdown of mARC1 in mice significantly reduced liver steatosis and fibrosis in multiple mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis. Furthermore, RNA-seq analysis revealed that the pathways involved in extracellular matrix remodeling and collagen formation were downregulated in the liver, and the plasma lipidome was significantly altered in response to the loss of mARC1 in mice. CONCLUSIONS: Overall, we have demonstrated that loss of mARC1 alters hepatocyte response to lipotoxic stress and protects mice from diet-induced MASH and liver fibrosis consistent with findings from human genetics.