Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue

Abstract

The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)␣ and LXR␤ have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR͞retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.L iver X receptor (LXR)␣ and LXR␤ have emerged as important regulators of lipid and lipoprotein metabolism. The LXRs are activated by physiological concentrations of oxidized derivatives of cholesterol such as 22(R)-hydroxycholesterol, 27-hydroxycholesterol, and 24(S),25-epoxycholesterol (1-3). LXR␣ is expressed at particularly high levels in liver, adipose tissue, and macrophages, whereas LXR␤ is expressed ubiquitously. These ligand-activated transcription factors form obligate heterodimers with the retinoid X receptor (RXR) and regulate the expression of target genes containing LXR response elements (LXREs). All the LXREs identified thus far are DR-4 hormone response elements (direct repeat of the consensus AGGTCA separated by four nucleotides) (4).To date, more than a dozen LXR target genes have been identified (5). In the liver, LXRs regulate expression of a number of proteins involved in cholesterol and fatty acid metabolism, including CYP7A and sterol regulatory binding element protein 1c (SREBP-1c) (6, 7). In macrophages and other peripheral cells, LXRs have been implicated in the reverse cholesterol transport pathway. LXRs control the transcription of several genes involved in cellular cholesterol efflux including ATP-binding cassette (ABC)A1, ABCG1, and apolipoprotein E (8-11). LXRs also seem to influence lipoprotein metabolism through the c...

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…In this work we found that NR1HR agonists increased basal glucose uptake in brown adipocytes in a dosedependent manner, in agreement with the results obtained in 3T3-L1 adipocytes [8]. This effect is the result of changes of SLC2A4 in the plasma membrane, and could be attributed to the activation of PKCζ and/or the increase in Slc2a4 expression produced by T0901317.…”

“…The effect of NR1HR agonists on Slc2a4 expression in rat brown adipocytes is in agreement with the up-regulation of Slc2a4 detected in murine and human adipocytes, where the Slc2a4 promoter is a direct transcriptional target for the NR1HR/RXR heterodimer [8,13]. On the other hand, T0901317 treatment did not produce insulin sensitisation, either on glucose uptake, or in the insulin signalling cascade, an effect clearly different from that observed for rosiglitazone in our previous work [19] and in studies performed in murine adipocytes [8]. Differential effects of pharmacological NR1HR activation on insulin sensitivity in normal or insulin-resistant conditions have also been detected in other studies.…”

“…We have recently proposed that rosiglitazone activates basal glucose uptake in a manner dependent on p38MAPK [19], and in some cellular systems PKC phosphorylation has been found to be increased by other nuclear receptor agonists such as vitamin D analogues [31]. The effect of NR1HR agonists on Slc2a4 expression in rat brown adipocytes is in agreement with the up-regulation of Slc2a4 detected in murine and human adipocytes, where the Slc2a4 promoter is a direct transcriptional target for the NR1HR/RXR heterodimer [8,13]. On the other hand, T0901317 treatment did not produce insulin sensitisation, either on glucose uptake, or in the insulin signalling cascade, an effect clearly different from that observed for rosiglitazone in our previous work [19] and in studies performed in murine adipocytes [8].…”

“…Moreover, ligand activation of NR1HR regulates production of the insulin-responsive glucose transporter solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) both in vivo and in murine and human adipocytes, through direct interaction with a conserved NR1HR response element in the Slc2a4 promoter. By contrast, the ability of NR1HR ligands to regulate SLC2A4 production was abolished in mice lacking Nr1h3 [8,13].…”

“…Although NR1HR function has been elucidated in detail with respect to cholesterol and lipid metabolism, new findings have indicated that NR1HR is an important regulator of glucose metabolism in liver and adipose tissue [3][4][5]. Recent studies have reported low plasma glucose, improved glucose tolerance and increased glucose-induced insulin secretion by islets in genetic and dietary models of type 2 diabetes treated with synthetic NR1HR agonists [6][7][8].…”