TC-E 5003 Reduces Hepatic Triglyceride Accumulation in Western Diet-Fed LDL Receptor Knockout and APOE*3-Leiden.CETP Mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by accumulation of lipids within hepatocytes. Conflicting evidence exists regarding the role of protein arginine methyltransferase 1 (PRMT1) in MASLD. Here we investigated the outcome of MASLD treatment with the PRMT1 inhibitor TC-E 5003 in mice fed a Western high-fat/high cholesterol diet. Chronic exposure of male low-density lipoprotein receptor knockout mice to 10 mg/kg TC-E 5003 reduced hepatic triglyceride levels (−37%; p < 0.05) and gene expression levels of the lipogenic factors SREBP-1 (−44%; p < 0.05) and FASN (−42%; p < 0.05). In addition, TC-E 5003 lowered pro-atherogenic very-low-density and low-density lipoprotein concentrations and reduced aortic macrophage foam cell accumulation. However, chronic treatment with 10 mg/kg TC-E 5003 was also associated with unexpected toxicity and mortality. A follow-up study in female APOE*3-Leiden.CETP mice showed that chronic treatment with 2.5 mg/kg TC-E 5003 was also associated with a significant reduction in hepatic triglyceride stores (−24%; p < 0.05) in the absence of adverse effects. Radiolabeled lipoprotein flux studies uncovered a 2-fold increase (p < 0.05) in brown adipose tissue triglyceride-derived fatty-acid uptake upon TC-E 5003 treatment, although the contribution of specific PRMT1 inhibition to this effect could not be established. In conclusion, TC-E 5003 consistently reduced hepatic triglyceride accumulation in two mouse models of metabolic dysfunction-associated steatotic liver disease. While the precise contribution of PRMT1 inhibition remains to be established, the present findings demonstrate that treatment with TC-E 5003 exerts robust steatosis-lowering effects in vivo and warrant further investigation as a potential therapeutic approach for MASLD.