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| Hepatocytes: Glucose comes into the eLiXiR
The membrane protein Klotho directly binds fibroblast growth factor 23 (FGF23) and determines the ligand specificity of FGF receptor 1 (FGFR1). The conversion of glucose into glycogen and fatty acids is controlled via a complex network of insulin signaling. In hepatocytes, the heterodimeric nuclear receptor and transcription factor liver X receptor (LXR) is known to connect glucose metabolism and lipogenesis. Besides controlling lipogenesis through the regulation SREBP-1c expression, LXR activation attenuates diabetes by decreasing liver glucose output. It has been suggested that hepatocytic glucose also directly influences its own metabolic fate independent of insulin mediation. A downstream effect of this proposed influence is the regulation of ChREBP's transcription factor activity, but the initial steps and confirmation of this pathway have remained elusive. Mitro et al. now report in Nature that glucose directly binds to LXR leading to an upregulation of the genes participating in lipogenesis.
Mitro et al. transfected human hepatocellular carcinoma cells with the LXR receptor and found that glucose and glucose-6-phosphate increased LXR transcriptional activity about 8-fold. Using purified LXR-ligand binding domain (LXR-LBD) for in vitro binding assays the authors found that the two early intermediates of glycolysis could displace both synthetic ligand or radiolabeled glucose from LXR. This demonstrates that both glucose and glucose-6-phosphate can directly bind to LXR. Importantly, these effects were not observed with other glycolysis intermediates. As to the physiological relevance of these results, Mitro et al. found that upon glucose binding to LXR the expression of cholesterol homeostasis genes increased, thus explaining the insulin-independent response of LXR to glucose. Furthermore, both glucose and a synthetic LXR ligand were able to stimulate the expression of genes involved in fatty acid synthesis while repressing gluconeogenic genes. To elucidate the functions of glucose binding to LXR in vivo, the authors offered glucose as the sole source of carbohydrate to fasted mice. Hepatocyte gene expression in these mice reflected the cell line observations. Additionally, hepatocytes from mice rendered insulin-deficient by streptozotocin injection still expressed LXR-dependent genes, affirming the hypothesis that glucose can act on LXR independently of insulin. Based on the results of their study, Mitro et al. hypothesize that glucose is also the ligand for LXR in the insulin-mediated activation of SREBP-1c leading to the promotion of lipogenesis. Direct and insulin-mediated glucose binding to LXR would explain the observation that low-fat, high-carbohydrate diets can cause high levels of triglycerides in blood. Finally, as LXR is the sensor for excess cholesterol, its function as a glucose sensor provides a molecular link for the observed connection between hyperglycemia and atherosclerosis. Mirko von Elstermann
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