1. Academic Validation
  2. PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

  • Sci Rep. 2022 Jan 10;12(1):483. doi: 10.1038/s41598-021-04524-w.
Laura M de Jong 1 Zhengzheng Zhang 2 Yvette den Hartog 1 Timothy J P Sijsenaar 1 Renata Martins Cardoso 1 Martijn L Manson 1 Thomas Hankemeier 2 Peter W Lindenburg 2 3 Daniela C F Salvatori 4 5 Miranda Van Eck 1 Menno Hoekstra 6
Affiliations

Affiliations

  • 1 Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands.
  • 2 Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
  • 3 Research Group Metabolomics, Leiden Center for Applied Bioscience, University of Applied Sciences Leiden, Leiden, The Netherlands.
  • 4 Central Laboratory Animal Facility, Leiden University Medical Center, Leiden, The Netherlands.
  • 5 Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • 6 Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands. hoekstra@lacdr.leidenuniv.nl.
Abstract

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 Inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on Cholesterol and bile acid metabolism can be effectively tackled.

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