Role of LXRs in control of lipogenesis

Schultz, Joshua R.; Tu, Hua; Luk, Alvin; Repa, Joyce J.; Medina, Julio C.; Li, Leping; Schwendner, Susan W.; Wang, Shelley; Thoolen, Martin; Mangelsdorf, David J.; Lustig, Kevin D.; Shan, Bei

doi:10.1101/gad.850400

Cited by 1,503 publications

(1,489 citation statements)

References 37 publications

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“…These are the key processes leading to the production of TGs that are known to be regulated by LXR (Schultz et al ., 2000) (Figure 3A). As previously described by Chisholm et al .…”

Section: Resultsmentioning

confidence: 99%

“…However, the LXR also regulates de novo hepatic lipogenesis via activation of the transcription factor sterol regulatory element‐binding protein 1c (SREBP1c) and direct interaction with hepatic lipogenic genes (Joseph et al ., 2002a; Talukdar and Hillgartner, 2006; Cha and Repa, 2007). As a result, LXR activation by the use of LXR agonists leads to unwanted hepatic steatosis (Schultz et al ., 2000; Grefhorst et al ., 2002). This steatotic effect of LXR agonism has hampered the development of LXR agonists for clinical use in humans.…”

Section: Introductionmentioning

confidence: 99%

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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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“…These are the key processes leading to the production of TGs that are known to be regulated by LXR (Schultz et al ., 2000) (Figure 3A). As previously described by Chisholm et al .…”

Section: Resultsmentioning

confidence: 99%

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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“…Yet double knockout mice (LXR -/-, -/-) have a greater accumulation of cholesterol, suggesting some functional overlap (Alberti et al 2001). Pharmacologic activation of LXRs activates lipogenic genes, sterol regulatory element binding protein 1c, SREBP-1c; fatty acid synthase, FAS; and steroyl-CoA desaturase 1, SCD-1-and elevates both hepatic and plasma triglyceride levels (Peet et al 1998;Schultz et al 2000).…”

Section: Lxrsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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“…Oxysterols are natural ligands for LXR [3][4][5][6]. A few non-steroidal synthetic LXR agonists have been developed, including T0901317 [7] and GW3965 [8]. T0901317 is the most commonly used LXR agonist for investigating physiological roles of the LXRs.…”

Section: Introductionmentioning

confidence: 99%

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

Chuu

Chen

Hiipakka

et al. 2007

Biochemical and Biophysical Research Communications

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T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells.

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Role of LXRs in control of lipogenesis

Cited by 1,503 publications

References 37 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

Nuclear receptors, mitochondria and lipid metabolism

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

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