Leiden University Scholarly Publications

Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux. However, current clinical application of these agents is hampered by the 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 the capacity of LXR to modulate 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, in absence and presence of the allosteric PRMT3 inhibitor SGC707.

Treatment with the PRMT3 inhibitor SGC707 did not negatively influence the T0901317/palm oil induced upregulation of the cholesterol efflux 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 FAS (-64%; p<0.01). A similar trend was observed for ACC (-56%) and SCD1 expression (-43%). This obstruction of lipogenic gene transcription coincided with a significant 2.3-fold (p<0.01) decrease in liver triglyceride content as compared to the T0901317 and palm oil treated control group.

Inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR-driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on cholesterol efflux pathways is maintained.