Loss of hepatic ME1 ameliorates MASLD by Suppressing peroxisomal β-Oxidation and Activating Lipophagy/Lipolysis

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an increasing global health problem in association with obesity and insulin resistance without approved pharmacotherapy. Previous studies revealed malic enzyme 1 (ME1) as a susceptibility gene for metabolic disorders in humans. However, the role and mechanisms of ME1 in regulating hepatic lipid metabolism remain largely unclear. OBJECTIVES: This study aimed to investigate the roles, mechanisms, and therapeutic potential of ME1 in regulating MASLD. METHODS: Hepatic expression of ME1 gene and protein were characterized in MASLD patients and three MASLD mouse models. Using a hepatocyte-specific Me1 knockout model, we assessed the effects of the gene on diet-induced or age-dependent MASLD. Oleic and palmitic acids were used to mimic hepatic lipid accumulation in vitro. Molecular mechanisms underlying ME1 function were investigated through RNA sequencing, biochemical analyses, and pharmacological intervention. RESULTS: . These changes ultimately enhanced the activation of mTORC1-dependent lipophagy and ATGL-dependent lipolysis respectively, resulting in the protection against MASLD. CONCLUSIONS: Our study provides the first demonstration that ME1 regulates ACOX1-mediated peroxisomal β-oxidation and subsequent lipophagy/lipolysis, revealing its pivotal lipid-regulatory role in MASLD. These findings underscore ME1 as a promising target for treating MASLD and associated liver pathologies.