共查询到20条相似文献,搜索用时 46 毫秒
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Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. 总被引:28,自引:0,他引:28
Sean B Joseph Bryan A Laffitte Parthive H Patel Michael A Watson Karen E Matsukuma Robert Walczak Jon L Collins Timothy F Osborne Peter Tontonoz 《The Journal of biological chemistry》2002,277(13):11019-11025
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Hee-jin Jun Minh-Hien Hoang Siok-Koon Yeo Yaoyao Jia Sung-Joon Lee 《Bioorganic & medicinal chemistry letters》2013,23(2):579-583
We investigated the effect of cineole on the expression of genes related to reverse cholesterol transport and hepatic fatty acid metabolism. Cineole, a small aroma compound in teas and herbs, significantly stimulated the transactivation of liver X receptor modulator (LXR)-α and LXR-β. The mRNA and protein expression of LXRs and their target genes, including ABCA1 and ABCG1, was significantly increased in macrophages stimulated with cineole. This led to the subsequent removal of cholesterol from the cells. Interestingly, cineole showed tissue-selective LXR induction: hepatocytes stimulated with cineole showed significantly reduced expression of LXR-α and LXR-α-responsive genes, including FAS and SCD-1 (P <0.05). Accordingly, hepatocytes treated with cineole displayed reduced cellular lipid accumulation compared with control cells, as assessed by Oil Red O lipid staining and cholesterol quantification. These results suggest that cineole is a selective LXR modulator that regulates the expression of key genes in reverse cholesterol transport in macrophages without inducing lipogenesis in hepatocytes. This selective LXR modulator may have practical implications for the development of hypocholesterolemic or anti-atherosclerotic agents and also suggests. 相似文献
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Kajikawa T Kataoka K Sakurai T 《Biochemical and biophysical research communications》2012,421(1):152-156
We have previously reported that liver X receptor (LXR) agonist, TO901317, could significantly inhibit hepatic apolipoprotein M (apoM) expression. It has been reported that TO901317 could activate the ATP-binding cassette transporter A1 (ABCA1) that mediates cholesterol efflux to the lipid-poor apoAI, which is an essential step for the high-density lipoprotein (HDL) formation. It is unknown if ABCA1 may regulate hepatic apoM expression. In the present study, HepG2 cells were cultured with the synthetic LXR agonists, TO901317 or GW3965 in the presence or absence of ABCA1 antagonist, disodium 4,4'-diisothiocyanatostilbene- 2,2'-disulfonate (DIDS). The mRNA levels of ABCA1, apoM and liver receptor homolog-1 (LRH-1) determined by the real-time RT-PCR. It demonstrated that both TO901317 and GW3965 could significantly enhance ABCA1 expression, and simultaneously, inhibit LRH1 expression. However, TO901317 alone could significantly inhibit apoM expression, while GW3965 alone did not influence apoM expression. ABCA1 antagonist, DIDS, have no effects on GW3965 induced upregulation of ABCA1 and downregulation of LRH1. However, apoM mRNA level was significantly decreased when the cells cultured with GW3965 together with DIDS. The present study demonstrated that apoM expression could be elevated by ABCA1 via the RXR/LXR pathway and LRH1 does not involve in the regulation of apoM by the activation of ABCA1, although the direct regulative pathway(s) between ABCA1 and apoM gene is still unknown yet. The detailed mechanism needs further investigation. 相似文献
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Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression 总被引:7,自引:0,他引:7
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Wagner BL Valledor AF Shao G Daige CL Bischoff ED Petrowski M Jepsen K Baek SH Heyman RA Rosenfeld MG Schulman IG Glass CK 《Molecular and cellular biology》2003,23(16):5780-5789
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Liver X receptor (LXR) ligands are currently being evaluated as potential therapeutic agents for the treatment of low HDL. The LXR ligand T0901317 elevates ATP binding cassette transporter A1 (ABCA1) and HDL levels in animal models and induces moderate lipogenesis through upregulation of sterol regulatory element binding protein 1c (SREBP1c). Because insulin may also regulate lipogenesis through SREBP1c and fatty acid synthase (FAS), we investigated the effect of an LXR ligand in hyperinsulinemic mice. Administration of T0901317 to male db/db mice for 12 days resulted in a more severe hypertriacylglycerolemia and hepatic triacylglycerol accumulation than observed in nondiabetic mice. The LXR target genes ABCA1, SREBP1c, FAS, and stearoyl-CoA desaturase 1 were upregulated by T0901317 treatment in both diabetic db/db and nondiabetic C57BLKS mice. Changes in lipogenic gene expression were independent of mouse strain, indicating that the severe lipogenesis observed in LXR ligand-treated db/db mice was not due to additive effects of insulin on lipogenic gene expression. Phosphoenolpyruvate carboxykinase expression was suppressed, suggesting that a shift from gluconeogenesis toward lipogenesis could partially explain our observations in db/db mice. Our data suggest that LXR ligands that have effects on both fatty acid and carbohydrate metabolism should be carefully evaluated in obesity, insulin, and leptin resistance. 相似文献
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The liver X receptors (LXRalpha and beta) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Insight into the physiologic roles of the LXRs has been greatly facilitated by the discovery of potent synthetic agonists. Here we show that one of these compounds, T0901317, is also a high-affinity ligand for the xenobiotic receptor pregnane X receptor (PXR). T0901317 binds and activates PXR with the same nanomolar potency with which it stimulates LXR activity. T0901317 induces expression not only of LXR target genes, but also of PXR target genes in cells and animals, including the scavenger receptor CD36, a property not shared by more specific LXR ligands, such as GW3965. Activation of PXR targets may explain why T0901317 induces dramatic liver steatosis, while GW3965 has a milder effect. These results suggest that many of the biological activities heretofore associated with LXR activation may be mediated by PXR, not LXR. Since T0901317 has been widely used in animals to study LXR function, the in vivo effects of this compound ascribed to LXR activation should be re-examined. 相似文献
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Reschly EJ Ai N Welsh WJ Ekins S Hagey LR Krasowski MD 《The Journal of steroid biochemistry and molecular biology》2008,110(1-2):83-94
Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRalpha and LXRbeta from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity. 相似文献
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Xiaolong Liang Yi Cao Song Xiang Zheng Xiang 《Journal of cellular biochemistry》2019,120(10):17391-17404
Liver X receptors (LXRs) are members of the nuclear receptor family, including the LXRα (NR1H3) and LXRβ (NR1H2) subtypes, which are related to the metabolism of glucose and cholesterol and possess anti-inflammatory functions. Mounting evidence has linked LXRs to the inhibition of cell proliferation in a variety of cancers. We revealed a differential distribution for NR1H3, but not for NR1H2, in colorectal cancer and adjacent normal tissues. We found that NR1H3 enhanced the inhibitory action of GW3965, an agonist of LXRs, on the proliferation of colorectal cancer cells. Upregulation of NR1H3 enhanced the inhibition of cell proliferation by GW3965 while silencing of NR1H3 attenuated the inhibitory effect of GW3965 on cell proliferation. Bioinformatic prediction and luciferase assays showed that NR1H3 was able to inhibit the activity of the epidermal growth factor receptor (EGFR) promoter. Moreover, we demonstrated that activation of NR1H3 inhibited the growth of transplanted tumors in an animal experiment, with the inhibition accompanied by downregulation of EGFR. Our findings suggest that NR1H3 controls cell proliferation by affecting EGFR promoter activity. The high expression of EGFR was due to the downregulation of NR1H3 which is a novel molecular mechanism in the development of colorectal cancer. 相似文献
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Quinet EM Savio DA Halpern AR Chen L Miller CP Nambi P 《Journal of lipid research》2004,45(10):1929-1942
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A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. 总被引:7,自引:0,他引:7
Carl P Sparrow Joanne Baffic My-Hanh Lam Erik G Lund Alan D Adams Xuan Fu Nancy Hayes A Brian Jones Karen L Macnaul John Ondeyka Sheo Singh Jianhua Wang Gaochao Zhou David E Moller Samuel D Wright John G Menke 《The Journal of biological chemistry》2002,277(12):10021-10027
The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels. 相似文献