MTARC1 Inactivation Remodels Lipid Droplets to Protect Against Metabolic Fatty Liver Disease.

Abstract

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden with limited treatment options. Human genetic studies have identified mitochondrial amidoxime-reducing component (MTARC1) variants associated with a reduced risk of MASLD, but the underlying mechanisms remain unclear. Here, we investigated the role of MTARC1 in fatty liver disease using in vitro and in vivo models. METHODS: We generated global and liver-specific Mtarc1 knockout mice, as well as models with genetic inhibition of Pnpla2, Lipa, Pemt and Cept1. We performed comprehensive biochemical, histological and integrated multi-omics analyses. In vitro cell culture models were used to delineate the mechanism by which MTARC1 regulates lipid metabolism. RESULTS: Global and liver specific knockout of Mtarc1 significantly protected against diet-induced hepatic triglyceride accumulation, liver injury, inflammation, and fibrosis. These effects required triglyceride degradation via lipophagy and lipolysis. Multi-omics profiling revealed that MTARC1 deficiency post-transcriptionally upregulates glycerophospholipid (GPL) biosynthetic enzymes CEPT1 and PEMT, leading to altered phospholipid composition in lipid droplets. This remodelling reduced the size of lipid droplets (LD), increased their surface-to-volume ratio, and thereby enhanced their degradation. Knockdown of CEPT1 and PEMT reversed the hepatoprotective effects of MTARC1 deficiency. CONCLUSIONS: Our findings identify an MTARC1-GPL biosynthesis-LD degradation axis as a key regulator of hepatic triglyceride homeostasis and highlight MTARC1 inhibition as a promising therapeutic strategy for MASLD.