TC-E 5003 Reduces Hepatic Triglyceride Accumulation in Western Diet-Fed LDL Receptor Knockout and APOE*3-Leiden.CETP Mice
- 1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands
- 2Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333ZA Leiden, The Netherlands
- 3Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands
Abstract
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.
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BibTeX
@article{zhang20265003,
title = {{TC-E 5003 Reduces Hepatic Triglyceride Accumulation in Western Diet-Fed LDL Receptor Knockout and APOE*3-Leiden.CETP Mice}},
author = {Yiheng Zhang and Timothy J. P. Sijsenaar and Ezra J. van der Wel and Amanda C. M. Pronk and Patrick C. N. Rensen and Sander Kooijman and Miranda Van Eck and Menno Hoekstra},
journal = {Biomolecules},
year = {2026},
month = nov,
doi = {10.3390/biom16111598},
url = {https://www.mdpi.com/2218-273X/16/11/1598},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TC-E 5003 Reduces Hepatic Triglyceride Accumulation in Western Diet-Fed LDL Receptor Knockout and APOE*3-Leiden.CETP Mice
AU - Yiheng Zhang
AU - Timothy J. P. Sijsenaar
AU - Ezra J. van der Wel
AU - Amanda C. M. Pronk
AU - Patrick C. N. Rensen
AU - Sander Kooijman
AU - Miranda Van Eck
AU - Menno Hoekstra
PY - 2026
DA - 2026/11/02
JO - Biomolecules
DO - 10.3390/biom16111598
UR - https://www.mdpi.com/2218-273X/16/11/1598
AB - 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.
SN - 2218-273X
ER -