The nuclear receptor LXR is a glucose sensor

Genomics Institute of the Novartis Research Foundation, 10675 John Hopkins Drive, San Diego, California 92121, USA.
Nature (Impact Factor: 41.46). 02/2007; 445(7124):219-23. DOI: 10.1038/nature05449
Source: PubMed


The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-alpha and LXR-beta. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.

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    • "Liver X receptors (LXR) belong to the nuclear receptor superfamily that regulates DNA transcription (Wojcicka et al. 2007). Transcriptional activity of LXR is regulated by binding to its natural ligands, most of which are oxygenated metabolites of cholesterol (i.e., oxysterols) (Mitro et al. 2007), and by interaction with additional co-regulatory proteins. Some of these co-regulatory proteins directly regulate epigenetic changes, including the SWItch/Sucrose Non-Fermentable chromatin-remodeling factors that induce changes in DNA methylation and promote transcriptional activation (Kim et al. 2012; O'Malley et al. 2008; Rosenfeld et al. 2006; Banine et al. 2005). "
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    ABSTRACT: The liver X receptor agonist, GW3965, improves cognition in Alzheimer's disease (AD) mouse models. Here, we determined if short-term GW3965 treatment induces changes in the DNA methylation state of the hippocampus, which are associated with cognitive improvement. Twenty-four-month-old triple-transgenic AD (3xTg-AD) mice were treated with GW3965 (50 mg/kg/day for 6 days). DNA methylation state was examined by modified bisulfite conversion and hybridization on Illumina Infinium Methylation BeadChip 450 k arrays. The Morris water maze was used for behavioral analysis. Our results show in addition to improvement in cognition methylation changes in 39 of 13,715 interrogated probes in treated 3xTg-AD mice compared with untreated 3xTg-AD mice. These changes in methylation probes include 29 gene loci. Importantly, changes in methylation status were mainly from synapse-related genes (SYP, SYN1, and DLG3) and neurogenesis-associated genes (HMGB3 and RBBP7). Thus, our results indicate that liver X receptors (LXR) agonist treatment induces rapid changes in DNA methylation, particularly in loci associated with genes involved in neurogenesis and synaptic function. Our results suggest a new potential mechanism to explain the beneficial effect of GW3965.
    Journal of Molecular Neuroscience 11/2015; DOI:10.1007/s12031-015-0665-8 · 2.34 Impact Factor
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    • "We found that knock down of SCAP reduced glucose-mediated activation of SREBP-1 and SREBP-2 (Figure 1H). Because liver X receptor (LXR), a member of the nuclear receptor family of transcription factors, promotes the expression of SREBP-1c upon activation (Repa et al., 2000), and glucose is reported to activate LXR in hepatocytes (Mitro et al., 2007), we sought to examine whether LXR possibly involves in glucose-activated SCAP/SREBP signaling. As shown in Figures S1A–S1C, our data show that both the protein and mRNA levels of ATP-binding cassette activating proteins ABCA1 and ABCG1, which are major downstream targets of LXR (Zelcer and Tontonoz , 2006), were not significantly upregulated by glucose supplement in U87 cells within 12 hr, demonstrating that LXR was not strongly activated by glucose in GBM cells. "
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    ABSTRACT: Tumorigenesis is associated with increased glucose consumption and lipogenesis, but how these pathways are interlinked is unclear. Here, we delineate a pathway in which EGFR signaling, by increasing glucose uptake, promotes N-glycosylation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and consequent activation of SREBP-1, an ER-bound transcription factor with central roles in lipid metabolism. Glycosylation stabilizes SCAP and reduces its association with Insig-1, allowing movement of SCAP/SREBP to the Golgi and consequent proteolytic activation of SREBP. Xenograft studies reveal that blocking SCAP N-glycosylation ameliorates EGFRvIII-driven glioblastoma growth. Thus, SCAP acts as key glucose-responsive protein linking oncogenic signaling and fuel availability to SREBP-dependent lipogenesis. Targeting SCAP N-glycosylation may provide a promising means of treating malignancies and metabolic diseases.
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    • "is and cell growth , through the activation of the sterol regulatory element - binding proteins , SREBP - 1c and SREBP - 2 ( Xu et al . , 2013 ) , and the carbohydrate responsive element - binding pro - tein , ChREBP ( Xu et al . , 2013 ) . SREBP - 1c and SREBP - 2 are under the control of the nuclear receptors called the liver X receptors ( LXR ; Mitro et al . , 2007 ; Figure 2 . A schematic and simplified representation of how natural dietary factors can direct cell metabolism toward oxidative meta - bolism ( on the left ) , biosynthesis ( on the right ) , and NF - kB - induced inflammation ( at the bottom of the figure , in red ) by their binding to nuclear receptors , transcription factors , and "
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    ABSTRACT: The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness. © The Author(s) 2015.
    ASN Neuro 02/2015; 7(1). DOI:10.1177/1759091414568185 · 4.02 Impact Factor
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