期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 175, 期 15, 页码 3175-3183出版社
WILEY
DOI: 10.1111/bph.14361
关键词
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资金
- Netherlands CardioVascular Research Initiative: Dutch Heart Foundation [CVON2011-19]
- Netherlands CardioVascular Research Initiative: Dutch Federation of University Medical Centers [CVON2011-19]
- Netherlands CardioVascular Research Initiative: Netherlands Organization for Health Research and Development [CVON2011-19]
- Netherlands Organization for Scientific Research (VICI) [91813603]
- Dutch Heart Foundation [2012T080]
- Netherlands Heart Foundation [2007T056]
- Netherlands CardioVascular Research Initiative: Royal Netherlands Academy of Sciences [CVON2011-19]
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY RESULTS 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 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 IMPLICATIONS We 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.
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