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

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.

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.

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.

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.