Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ

Repa, Joyce J.; Liang, Guosheng; Ou, Jiafu; Bashmakov, Yuriy K.; Lobaccaro, Jean Marc; Shimomura, Iichiro; Shan, Bei; Brown, Michael S.; Goldstein, Joseph L.; Mangelsdorf, David J.

doi:10.1101/gad.844900

Cited by 1,529 publications

(1,317 citation statements)

References 51 publications

Supporting

Mentioning

1,214

Contrasting

Unclassified

Order By: Relevance

“…The http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=602 (LXR) is a nuclear oxysterol receptor, which functions as a transcriptional regulator of genes involved in lipid metabolism (Repa et al ., 2000). Active LXR regulates cholesterol absorption, transport and catabolism (Venkateswaran et al ., 2000; Yu et al ., 2003).…”

Section: Introductionmentioning

confidence: 99%

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

Nahon

Groeneveldt

Geerling

et al. 2018

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Nahon

Groeneveldt

Geerling

et al. 2018

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…RXRs are capable of activating transcription either as homodimers or as the heterodimeric partner of other nuclear receptors [8]. Two groups [9,10] reported a RXR ligand-dependent increase in triglyceride/fatty acid synthesis due to enhanced expression of the LXR/RXR target gene, SREBP-1c, a well-established activator of lipogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, RXR agonists induced SREBP-1 expression in mouse [9] and HepG2 cells [10]. However, the latter study was performed with 10% FCS, which may interfere with the RA treatment.…”

mentioning

confidence: 99%

SREBP‐1c mediates the retinoid‐dependent increase in fatty acid synthase promoter activity in HepG2

2007

View full text Add to dashboard Cite

Treatment of HepG2 with all-trans retinoic acid (RA) induces expression of fatty acid synthase (FAS) mRNA and protein. Transfections show that the FAS promoter positively responds to retinoid X receptor (RXR) but not to RA receptor (RAR) agonists. Since RXR alone is capable of mediating the RA response of FAS, the existence of a classical RA-responsive element in the FAS promoter may be ruled out. Binding sites for NF-Y and SREBP-1 proved to be essential for the RA response. Exposure to all-trans RA increased mRNA and protein levels of SREBP-1, a transcriptional activator for FAS. Overexpression of a dominant-negative form of SREBP-1c diminished the RAdependent increase in promoter activity. These data demonstrate that RXR ligands can stimulate the expression of a lipogenic gene solely by inducing transcription and cleavage of membrane-bound SREBP-1c.

show abstract

“…Liver X receptor (LXRa) also belongs to nuclear receptor family, regulates genes coding for Apo-E, ATP binding cassette A1 (ABCAI) cholesterol transporter, sterol regulatory element binding protein (SREBP) and IL-8 which play crucial role in atherosclerosis [9][10][11]. Uptake of oxLDL uptake through CD36 provides the ligands not only for PPARs (a, c) but also for LXRa [12].…”

Section: Introductionmentioning

confidence: 99%

Importance of blood cellular genomic profile in coronary heart disease

2005

View full text Add to dashboard Cite

SummarySince receptor/transcription factor family especially peroxisome proliferator-activated receptors PPARs (a, c) and liver X receptor a (LXRa) have been recognized to play crucial role in both lipid metabolism and inflammation, the present study was addressed to explore the interrelationship between blood cellular genomic expression profile, serum lipid levels and severity of coronary heart disease (CHD) in human subjects. Based upon the demographic and laboratory data, the human subjects were divided into 4 groups. Genomic expression profile in the subjects belonging to these groups was determined by measuring the transcriptional expression of genes coding for PPARs (a, c), CD36, LXRa and low density lipoprotein receptor (LDLR) in their blood mononuclear cells. This genomic expression profile was correlated with serum lipid profile as well as with the severity of CHD (revealed by coronary angiography coupled with modified Gensini score) using standard statistical analytical methods. Further in vitro and in vivo effect of statins on such genomic profile was also explored. Although genes coding for PPARs (a, c), CD36, LDLR showed correlation with the severity of coronary atherosclerosis , blood cellular LXRa genomic profile showed conspicuous negative correlation with the severity of coronary atherosclerosis in subjects with or without hypercholesterolemia. This view was further confirmed in experiments directed to understand the effect of statins on the cellular genomic profile of PPARs (a, c) and LXRa. Based on these reported findings, we propose that blood cellular LXRa genomic profile has a protective effect against the development of CHD and hence may be of importance in devising synthetic therapeutic drugs for CHD in future.

show abstract

Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ

Cited by 1,529 publications

References 51 publications

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

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

SREBP‐1c mediates the retinoid‐dependent increase in fatty acid synthase promoter activity in HepG2

Importance of blood cellular genomic profile in coronary heart disease

Contact Info

Product

Resources

About