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

Abstract

Background and PurposeAgonists 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.Experimental ApproachA 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.Key ResultsTreatment 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 observed for stearoyl‐coenzyme A desaturase and acetyl CoA carboxylase expression (−43%; −56%). This obstruction of lipogenic gene transcription coincided with a significant 2.3‐fold decrease in liver triglyceride content as compared with the T0901317 and palm oil‐treated control group.Conclusion and ImplicationsWe showed that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR‐driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained.

Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648

“…However, the involvement of histone arginine methylation in the lineage commitment of MSCs remains unclear. PRMT3 catalyzes asymmetric dimethylation of H4R3 23,48,49 . We confirmed that H4R3 is a substrate of PRMT3 in MSCs.…”

“…Further studies are needed to explore the detailed mechanism of how PRMT3 affects the function of osteoclasts and thus regulates the process of bone resorption. Joya et al found that SGC707 treatment impairs the hepatic lipogenesis due to administration of LXR agonists as therapeutic agents for cholesterol-driven diseases in an in vivo animal study 49 . Our study revealed the effect of SGC707 on bone metabolism, which should be taken into consideration for clinical application.…”

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

“…The first described inhibitor of PRMT3, compound 1, exhibited allosteric binding and showed promise as an emerging therapy [ 129 ]. SGC707 was an analog that demonstrated improved selectivity and potency over the parent compound in pre-clinical testing of adenocarcinoma ( Table 2 ) [ 45 , 130 ].…”

Protein arginine methyltransferases and hepatocellular carcinoma: A review

“…In the mouse models of alcohol induced liver injury, PRMT1 protect hepatocytes from oxidative stress response [30 , 31] . PRMT3 is involved in hepatic lipogenesis by interacting with LXRα, and palmitic acid treatment induces PRMT3 translocation to the nucleus accompanied by increased transcriptional activity of LXRα in mouse models of NAFLD [32] , [33] , [34] . PRMT6 promotes fasting-induced activation of the gluconeogenic program dependent on CRTC2, and couples glucose availability with mitochondria biogenesis by mediating SIRT7 methylation [35 , 36] .…”