Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor-driven transcription of hepatic lipogenic genes in vivo

British Journal of Pharmacology
Joya E NahonMenno Hoekstra

Abstract

Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR-induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co-activator of LXR activity. Here, we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis while maintaining its capacity to modulate macrophage cholesterol homeostasis. A combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707. Treatment with SGC707 did not negatively influence the T0901317/palm oil-induced up-regulation of the cholesterol efflux ATP-binding cassette transporter genes, ABCA1 and ABCG1, in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene fatty acid synthase (-64%). A similar trend was ob...Continue Reading

References

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Citations

Dec 16, 2020·The Journal of Nutritional Biochemistry·Menno HoekstraMiranda Van Eck
Jan 15, 2021·Cells·Jean-Paul BryantYeshavanth Kumar Banasavadi-Siddegowda
Mar 21, 2021·Nature Reviews. Drug Discovery·Qin WuDalia Barsyte-Lovejoy
Aug 9, 2021·Translational Oncology·Yu LeiDean Tian

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Methods Mentioned

BETA
Protein Assay
PCR

Software Mentioned

Leica
Primer Express
ARRIVE
Leica Qwin Imaging
GraphPad Prism

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