Liver-specific mitochondrial amidoxime–reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models

Abstract

Background: Human genetic studies have identified several mitochondrial amidoxime–reducing component 1 (MTARC1) variants as protective against metabolic dysfunction–associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear. Methods: Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine–conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques. Results: In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction–associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction–associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet. Conclusions: Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction–associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.