The nuclear receptor LXR is a glucose sensor
ABSTRACT 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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- "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 "
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 · 4.44 Impact Factor
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- ") Glucose 6-phosphate (cytosol) g6p LXRa (DeBose-Boyd et al., 2001; Lehmann et al., 1997; Mitro et al., 2007) Fructose 2,6-bisphosphate (cytosol) f26p2 G6PC (Arden et al., 2012; Pedersen et al., 2007) Pyruvate (cytosol) pyruvate PDHK2 (Bowker-Kinley et al., 1998; Sugden and Holness, 2006) Xylulose 5-phosphate (cytosol) x5p PP2A (Kabashima et al., 2003) We divide the set S of signalling species into index subsets with respect to physiological meaning and state value calculation (cf. Supplementary Fig. S2 and Table S4 "
ABSTRACT: Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism.Biosystems 10/2014; 124. DOI:10.1016/j.biosystems.2014.07.002 · 1.47 Impact Factor
- "The fact that unsaturated fatty acids can function as LXR antagonists, and thereby create a feedback mechanism, supports this suggestion further (Ou et al., 2001). Additionally, LXRs have recently been implicated in negative regulation of inflammatory gene expression (Marathe et al., 2006), and as key regulators of genes governing carbohydrate metabolism (Mitro et al., 2007). "