Liver X Receptors Interact with Corepressors to Regulate Gene Expression

Hu, Xiao; Li, Suzhen; Wu, Jun; Xia, Chunsheng; Lala, Deepak S.

doi:10.1210/me.2002-0399

Cited by 130 publications

(105 citation statements)

References 37 publications

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“…Such nuclear proteins include co-activators and co-repressors. Unliganded LXR a and LXR b bind to co-repressors [Hu et al, 2003] and inhibit gene transcription. One of the described differences between LXR a and LXR b is their affinity to co-repressors.…”

Section: Discussionmentioning

confidence: 99%

“…One of the described differences between LXR a and LXR b is their affinity to co-repressors. Whereas LXR a binds co-repressors NCo-R and silencing mediator for retinoid and thyroid receptor (SMRT) strongly, LXR b interacts only weakly [Hu et al, 2003]. If co-repressors act as retention factors, these differences in affinity to co-repressors likely contribute to stronger nuclear retention of LXR a than of LXR b.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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Activity of nuclear receptors is regulated by their nuclear localization. Liver X receptors (LXR) a and b are nuclear receptors that regulate transcription of genes for cholesterol metabolism, cholesterol transport, and lipogenesis. While LXR a and b are very similar in structure and exhibit similar ligand binding properties, their physiological roles are quite different. Since the LXRs fall into a class of receptors that move between the nucleus and cytoplasm, experiments were conducted to determine whether LXR a and LXR b show differences in their nuclear localization pattern. To determine the location of each receptor, cell lines stably expressing yellow fluorescent protein (YFP) chimeras with either LXR a or LXR b were examined. Retention in the nucleus of the chimeric proteins in the presence or absence of ligands was assessed using fluorescence microscopy coupled with digitonin permeabilization assays. Surprisingly, differences were found between LXR a and LXR b. Whereas unliganded LXR a was retained in the nucleus, unliganded LXR b was partially exported. Mutations were then introduced into putative nuclear localization sequences (NLS) to determine which sequences are important for nuclear localization and function. Mutation in one such sequence abolished nuclear localization of LXR a, whereas the analogous change in LXR b had a much less dramatic effect. Mutations in analogous putative NLS also differentially affected transcriptional activation by LXR a and LXR b. These data demonstrate for the first time that nuclear retention and localization as well as function of LXR a and LXR b are differentially regulated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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“…If LXRs were mediating the effects of mevalonate depletion on fatty acid synthesis it would be unlikely that it was acting in its ligand-bound state. Transcriptional activity of LXR can be modulated in the absence of its ligand by altering its interaction with co-repressors of transcription; in the presence of excess repressors basal transcriptional activity of LXR is reduced (37). One of the transcriptional repressors of LXR is the small heterodimer partner (SHP) and was found to interact with LXR even in the absence of its ligand (38).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Murthy¹,

Tong²,

Hohl

2005

Journal of Biological Chemistry

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Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and its gene target, sterol regulatory element binding protein-1c (SREBP-1c). LXR activation is induced by oxysterol end products of the mevalonate pathway and is inhibited by the upstream non-sterol isoprenoid, geranylgeranyl pyrophosphate (GGPP). Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. In CaCo-2 colon epithelial cells, depletion of mevalonate and its derivatives, including oxysterol ligands for LXR, increased fatty acid synthesis. Addition of mevalonate or its isoprenoid derivative, farnesyl pyrophosphate (FPP), prevented this increase. The effects of FPP were likely due to itself or its degradation products, because none of its downstream derivatives, GGPP, ubiquinone, or cholesterol, were effective. Moreover, the effects of FPP could not be accounted for by protein prenylation, because inhibition of farnesylation did not alter fatty acid synthesis in mevalonate-depleted cells incubated with the isoprenoid. Neither was fatty acid synthesis in these cells altered by inhibition of ␤-oxidation. Mevalonate depletion increased fatty acid synthase (FAS) mRNA by transcriptional mechanisms, without increasing gene expression of other enzymes involved in fatty acid biosynthesis or of SREBP-1c. The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion. FPP prevented the increase in FAS mRNA in mevalonate-depleted cells without altering SREBP-2 activation. Thus, FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway.The biosynthesis of fatty acids and cholesterol are closely related. Enzymes catalyzing the synthesis and metabolism of both lipids are coordinately regulated by the same transcription factors, the sterol regulatory element-binding proteins (SREBPs) 2 and the liver X receptors (LXRs) (1-3). LXRs belong to a superfamily of nuclear hormone receptors that are ligand-activated transcription factors (3). They form obligate heterodimers with retinoid X receptors (RXRs), another member of this receptor family, and subsequently bind to specific response ele-

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“…Modifying cofactor availability or functionality could therefore provide a tool to selectively control LXR‐mediated transcription. In the absence of an LXR agonist, LXR‐dependent transcription is inhibited by the recruitment of co‐repressors (Hu et al ., 2003). LXR activation by ligands results in the dissociation of the co‐repressor and moderate activation of target gene transcription.…”

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

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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.

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Liver X Receptors Interact with Corepressors to Regulate Gene Expression

Cited by 130 publications

References 37 publications

Nuclear localization of liver X receptor α and β is differentially regulated

Nuclear localization of liver X receptor α and β is differentially regulated

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

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

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