MTARC1 Regulates Lipid Droplet Degradation via Phospholipid Remodeling in Metabolic Fatty Liver Disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of liver disease, including simple fatty liver, hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, with limited treatment options. MTARC1 p.A165T variant is associated with reduced risk of MASLD. We previously showed that this variant promotes MTARC1 protein degradation, suggesting MTARC1 inactivation may represent a potential therapeutic strategy. Here, we report that global or liver specific Mtarc1 knockout markedly suppresses diet-induced hepatic TG accumulation, liver injury, inflammation, and fibrosis in a manner dependently on lipolysis and lipophagy. MTARC1 inactivation post-transcriptionally upregulates PEMT and CEPT1 expression, consequently elevating GPL levels, including PC, PE, and lyso-PE, three major GPLs of hepatic LDs. Furthermore, we observed that MTARC1-deficient hepatocytes exhibited smaller but more numerous LDs compared to controls, under comparable cellular TG levels during lipolysis/lipophagy inhibition. Importantly, inhibition of CEPT1 or PEMT could attenuated the hepatoprotective effect of MTARC1 deficiency. Mechanistically, subcellular GPL remodeling induced by MTARC1 deficiency reduce LD size while increase their surface-to-volume ratio, which in turn promote TG degradation through lipolysis and lipophagy. Collectively, our findings identify MTARC1-GPL biosynthesis-LD degradation axis as a key regulator of fatty liver disease and highlight MTARC1 inhibition as a promising therapeutic strategy for MASLD.