A central enzyme in the pathway of de novo lipogenesis, fatty acid synthase (FAS) 1 catalyzes all of the steps in the conversion of malonyl-CoA to palmitate. Expression of the FAS gene is controlled primarily at the level of transcription and is responsive to both hormonal and nutritional signals (1, 2). Previous work has shown that sterol regulatory element-binding proteins (SREBPs) play a critical role in the transcriptional regulation of a number of genes in the lipogenic pathway, including FAS, steroyl-CoA desaturase (SCD-1), and acetyl-CoA carboxylase (ACC) (3-8). Three SREBP isoforms have been described: SREBP-1a and Ϫ1c (also called ADD1), which are derived from the same gene through alternative splicing, and SREBP-2, which is encoded by a separate gene (9, 10). Although their transcriptional targets overlap significantly, studies suggest that SREBP-1 preferentially activates genes involved in lipogenesis, whereas SREBP-2 preferentially activates genes in the cholesterol biosynthetic pathway (11-14). SREBPs have been shown to regulate FAS expression through direct interaction with the FAS promoter at multiple sites (7, 15). Overexpression of nuclear SREBP-1 is sufficient to induce expression of the FAS gene in cultured cells as well as transgenic mice (5,8). Recent work has also implicated the nuclear receptors LXR␣ and LXR␤ in the control of lipogenesis. Both LXRs bind to DNA and regulate transcription of target genes in a heterodimeric complex with RXR (16). Although early studies on LXRs focused on their role in cholesterol metabolism, mice carrying a targeted disruption in the LXR␣ gene were noted to be deficient in expression of FAS, SCD-1, ACC, and SREBP-1, consistent with a role in lipogenesis as well (17). Further support for this idea came with the observation that the administration of the synthetic LXR ligand T1317 to mice triggers induction of the lipogenic pathway and raises plasma triglyceride levels (18). The demonstration that the SREBP-1c promoter is a direct target for regulation by LXR/RXR heterodimers provided a straightforward explanation for the ability of LXR ligands to induce hepatic lipogenesis (19,20). Until now, the effects of LXR activation on the expression of lipogenic genes, including FAS, have been presumed to be entirely indirect.We demonstrate here that the FAS promoter is a direct target for regulation by the LXR/RXR heterodimer as well as SREBPs. This novel mechanism for the regulation of FAS expression and lipogenesis by LXRs has implications for the development of LXR agonists as modulators of human lipid metabolism. EXPERIMENTAL PROCEDURESReagents and Plasmids-Expression plasmids for RXR␣ and LXR␣, and nuclear SREBP-1a, -1c, and -2 have been described (21,22). GW3965 (23) and T0901317 (18) were provided by Timothy M. Willson (GlaxoSmithKline). Ligands were dissolved in Me 2 SO prior to use in cell culture. The Ϫ1594, Ϫ700, Ϫ150, and Ϫ135 rat FAS promoter luciferase reporter constructs were described previously (3). Mutations were

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...

Recent studies have identified the liver X receptors (LXR␣ and LXR␤) as important regulators of cholesterol metabolism and transport. LXRs control transcription of genes critical to a range of biological functions including regulation of high density lipoprotein cholesterol metabolism, hepatic cholesterol catabolism, and intestinal sterol absorption. Although LXR activity has been proposed to be critical for physiologic lipid metabolism and transport, direct evidence linking LXR signaling pathways to the pathogenesis of cardiovascular disease has yet to be established. In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. Our results demonstrate that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identify LXRs as targets for intervention in cardiovascular disease.