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

Laura M De Jong,Renata Martins Cardoso,Zhengzheng Zhang,Miranda Van Eck,Thomas Hankemeier,Timothy J P Sijsenaar,Yvette Den Hartog,Daniela C F Salvatori,Peter W Lindenburg,Menno Hoekstra,Martijn L Manson

doi:10.1038/s41598-021-04524-w

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.

Highlights

Non-alcoholic fatty liver disease, the accumulation of lipids in the liver referred to as hepatic steatosis, is a pathological condition with a rapidly growing global incidence
The aim of this study was to verify that chronic treatment with the Protein arginine methyltransferase 3 (PRMT3) inhibitor SGC707 would inhibit hepatic triglyceride synthesis and the development of non-alcoholic fatty liver disease and, as a result, decrease the plasma hyperlipidemia extent and atherosclerosis susceptibility in Western diet-fed low density lipoprotein (LDL) receptor knockout mice
Biochemical and histological analysis on liver specimens showed that SGC707 treatment was associated with the expected decrease in lipogenic transcript levels as well as a diminished hepatic steatosis extent

Summary

Introduction

Non-alcoholic fatty liver disease, the accumulation of lipids in the liver referred to as hepatic steatosis, is a pathological condition with a rapidly growing global incidence. We anticipated that the SGC707-mediated decrease in the hepatic steatosis extent would be paralleled by a reduction in atherosclerosis susceptibility in our Western-type diet-fed apoE knockout mice, SGC707-treated mice exhibited a similar atherosclerosis burden as compared to solvent control-treated m ice[6]. Karasawa et al.[8] have shown, by modulating the activity of the lipogenic transcription factor sterol regulatory element-binding protein 1c, that hepatic triglyceride synthesis does contribute significantly to plasma lipid levels and atherosclerotic lesion formation in Western-type diet-fed low density lipoprotein (LDL) receptor knockout mice, another widely-used atherosclerosis mouse m odel[9]. In the present study we set out to assess the effect of chronic SGC707 treatment on the hepatic steatosis, hyperlipidemia and atherosclerosis extent in Western-type diet-fed LDL receptor knockout mice

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