核受体LXR在糖代谢中的作用

最新研究表明,核受体LXR是糖代谢的关键调节因子。LXR在肌肉和脂肪组织中通过葡糖转运蛋白(GLUT)使葡萄糖上调控,在肝脏中通过抑制重要的糖合成酶的表达来抑制糖合成。     

LXR对胆固醇稳态影响的研究进展

胆固醇是细胞膜的重要组成部分,构成生命的基本分子之一,也是胆汁酸和类固醇激素合成的底物,其代谢平衡受到诸多因素的精密调节.虽然胆固醇是细胞和人体生理功能所必需的,但血清总胆固醇增高可导致2型糖尿病、高胆固醇血症以及动脉粥样硬化等疾病.肝X受体(LXR)是一种重要的细胞核受体,是配体依赖的转录因子,包含LXRα和LXRβ两种亚型,LXRα在肝脏、小肠、巨噬细胞、脂肪组织中均有表达,而LXRβ有着广泛的表达.LXR与视黄醇类X受体结合后,形成异二聚体,刺激靶基因的表达.激活的LXR通过调节肠道对饮食胆固醇的吸收、肝脏对胆固醇的合成和降解以及胆汁酸的代谢,控制着胆固醇稳态.此外,LXR还参与调节脂肪形成、糖代谢、巨噬细胞的天然免疫和炎症反应等生理活动.因此,LXRs有望成为治疗动脉粥样硬化、阿尔茨海默氏等疾病的药物靶点.     

Establishment of a monoclonal antibody for human LXRα: Detection of LXRα protein expression in human macrophages

Liver X activated receptor alpha (LXRalpha) forms a functional dimeric nuclear receptor with RXR that regulates the metabolism of several important lipids, including cholesterol and bile acids. As compared with RXR, the LXRalpha protein level in the cell is low and the LXRalpha protein itself is very hard to detect. We have previously reported that the mRNA for LXRalpha is highly expressed in human cultured macrophages. In order to confirm the presence of the LXRalpha protein in the human macrophage, we have established a monoclonal antibody against LXRalpha, K-8607. The binding of mAb K-8607 to the human LXRalpha protein was confirmed by a wide variety of different techniques, including immunoblotting, immunohistochemistry, and electrophoretic mobility shift assay (EMSA). By immunoblotting with this antibody, the presence of native LXR protein in primary cultured human macrophage was demonstrated, as was its absence in human monocytes. This monoclonal anti-LXRalpha antibody should prove to be a useful tool in the analysis of the human LXRalpha protein.     

Discovery and SAR of cinnolines/quinolines as liver X receptor (LXR) agonists with binding selectivity for LXRβ

A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2′,3′ or 2′,5′-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRβ over LXRα. The LXRβ binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRα Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.     

LXR和ABCA1对体内胆固醇代谢的调节作用

肝外组织胆固醇返回肝脏,在肝脏通过生成胆汁酸排出,这一过程称为胆固醇逆转运。研究表明LXRs在维持体内胆固醇平衡方面起着感受器作用,通过关键靶基因转录的控制来调节胆固醇分解、储存、吸收和转运。LXR和RXR激动剂可上调巨噬细胞三磷酸腺苷结合盒转运体A1和G1(ABCAl,ABCGl)的表达,导致细胞内胆固醇流出。以LXR作为靶点的药物将为治疗高胆固醇血症和抗As提供新的希望。     

Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease

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The role of LXRα in goose primary hepatocyte lipogenesis

In this study, we investigate the role of liver X receptor alpha (LXR alpha) in lipogenesis in geese in order to understand the differences in hepatic steatosis mechanisms between mammals and waterfowl. Primary goose hepatocytes were isolated and treated with the LXR alpha agonist T0901317. Triglyceride (TG) accumulation, acetyl-CoA carboxylase alpha (ACC alpha) and fatty acid synthase (FAS) activities, and gene expression levels of LXR alpha, sterol regulatory element-binding proteins-1 (SREBP-1), FAS, ACC alpha and lipoprotein lipase (LPL) were measured in primary hepatocytes. We found a dose-dependent up-regulation of TG accumulation, ACC, and FAS activities and the mRNA levels of LXR alpha, SREBP-1, FAS, ACC alpha, and LPL genes in the presence of To-901317. We also found that binding of nuclear SREBP-1 to ACC alpha SRE sequence was induced by To-901317 (P < 0.05). In conclusion, LXR alpha is involved in the induction of the lipogenic pathway through activation of SREBP-1 and its target genes in goose primary hepatocytes.     

LXRα-mediated downregulation of EGFR suppress colorectal cancer cell proliferation

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.     

Lack of association between LXRα and LXRβ gene polymorphisms and prevalence of metabolic syndrome: A case–control study of an Iranian population

The metabolic syndrome (MetS) is considered to be a major risk factor for type 2 diabetes mellitus and cardiovascular diseases. It is characterized by central adiposity, high blood pressure, glucose intolerance and abnormalities of lipoprotein metabolism. The cause of MetS is likely to be due to a complex interaction between genetic and environmental factors. Liver X receptors alpha (NR1H3) and beta (NR1H2) play a key role in lipid and carbohydrate metabolism. The aim of this study was to investigate the contribution of genetic polymorphisms in the LXRs to risk of MetS and related traits. Two common SNPs in NR1H3 (rs11039155 and rs2279238) and in NR1H2 (rs17373080 and rs2695121) were genotyped using TaqMan assays in MetS patients (n = 265) and controls (n = 219). Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotypes with the presence of MetS and related phenotypes. Although The NR1H2 polymorphism rs2695121 was nominally associated with MetS but correction for multiple-testing and adjustment for age, sex and number of MetS criteria, failed to identify any significant interactions associated with prevalence of MetS. However in the haplotype analysis, a LXRα haplotype AC, was more common in controls and was associated with a significant protective effect for MetS (OR [95% CI] = 0.25 [0.07–0.88], p = 0.031). In conclusion, this study suggests that the above-named variants in LXRα and LXRβ genes are not potential contributors to the risk of MetS and related traits in an Iranian population.     

肺炎衣原体抑制LXRα-ABCA1途径促进巨噬细胞脂质蓄积

为探讨肝X受体α(LXRα)-三磷酸腺苷结合盒转运体A1(ABCA1)途径在肺炎衣原体(C.pneumoniae)促巨噬细胞脂质蓄积中的作用和机制,以THP-1巨噬细胞源性泡沫细胞为模型,采用高效液相色谱分析细胞内总胆固醇、游离胆固醇和胆固醇酯含量,液体闪烁计数器检测细胞内胆固醇流出,RT-PCR检测ABCA1和LXRαm RNA的表达,蛋白质印迹检测ABCA1和LXRα的蛋白质表达;使用LXRα的特异性激动剂T0901317对细胞进行预处理,再观察上述指标的变化.结果显示,C.pneumoniae可促进THP-1巨噬细胞源性泡沫细胞内总胆固醇、游离胆固醇和胆固醇酯含量增加,抑制胆固醇外流,降低细胞ABCA1和LXRα的表达;使用ABCA1激动剂8-溴-环磷酸腺苷预处理细胞或LXR激动剂T0901317预处理细胞后,可明显减弱C.pneumoniae对THP-1细胞ABCA1的表达抑制,促进细胞胆固醇流出,降低细胞内胆固醇的含量.结果提示,C.pneumoniae促进巨噬细胞脂质蓄积及胆固醇流出障碍,其机制可能与LXRα-ABCA1途径有关.     

Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice

The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRα) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxrα^-/- males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxrα^-/- males which display a female-like phenotype. We also show that circadian expression patterns of liver 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxrα^-/- animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxα^-/- females and could be explained by the change in corticosterone profile. Together this data indicates that LXRα is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRα in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRα targeted therapies.     

PPARγ and LXR Signaling Inhibit Dendritic Cell-Mediated HIV-1 Capture and trans-Infection

Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPARγ and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPARγ and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPARγ and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.     

LXR/RXR及ABCA1跨膜转运胆固醇体系与阿尔茨海默病

胆固醇代谢异常和Aβ沉积与阿尔茨海默病(AD)的发生发展密切相关。肝X受体(LXR)和类视黄醇X受体(RXR)介导的三磷酸腺苷结合盒A1(ABCA1)跨膜转运胆固醇体系在维持细胞内外胆固醇平衡中发挥重要作用,并参与Aβ的转运、沉积和老年斑的形成,其中的关键介导物质有望成为AD治疗的新靶点。