Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.

OBJECTIVE-Results from the Diabetes Control ComplicationsTrial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate Ͼ5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as "hyperglycemic memory." We have hypothesized that transient hyperglycemia mediates persistent geneactivating events attributed to changes in epigenetic information. RESEARCH DESIGN AND METHODS-Models of transienthyperglycemia were used to link NFB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFB-p65 chromatin. RESULTS-The sustained upregulation of the NFB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia.CONCLUSIONS-These studies indicate that the active transcriptional state of the NFB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes. Diabetes 58:1229-1236, 2009 V ascular complications are the major source of morbidity and mortality in diabetes and are considered, based on both epidemiological data and from more mechanistic studies, to occur primarily as a result of the long-term deleterious effects of hyperglycemia. Interestingly, these vascular complications often persist and may progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Results in both type 1 and type 2 diabetes, as observed in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study and in the recent follow-up of the U.K. Prospective Diabetes Study (UKPDS), have revealed that end-organ effects that occurred in both conventional and intensified glycemic control groups continued to operate Ͼ5 years after the patients had returned to their usual level of glycemic control (1,2). These studies suggest that the injurious effects of exposure to high glucose levels persist for many years after these episodes of altered metabolic control and this is typically referred to as either "hyperglycemic memory" (3) or the legacy effect (4). Recently, several clinical trials, including the ADVANCE (5) and ACCORD studies (6), failed to demonstrate that intensified glycemic control for 3-5 years markedly reduced ...

OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE Ϫ/Ϫ model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoEϪ/Ϫ and RAGE Ϫ/Ϫ / apoE Ϫ/Ϫ double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoEϪ/Ϫ mice showed increased plaque accumulation (14.9 Ϯ 1.7%), diabetic RAGE Ϫ/Ϫ /apoE Ϫ/Ϫ mice had significantly reduced atherosclerotic plaque area (4.9 Ϯ 0.4%) to levels not significantly different from control apoE Ϫ/Ϫ mice (4.3 Ϯ 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-B subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE Ϫ/Ϫ mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGECONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications. Diabetes 57:2461-2469, 2008 T he receptor for advanced glycation end products (RAGE) is a multiligand cell surface molecule belonging to the immunoglobulin superfamily (1). It is expressed as full-length, N-truncated, and C-truncated isoforms, generated in humans by alternative splicing (2). Activation of the full-length RAGE receptor has been implicated in a range of chronic diseases, including various diabetic complications and atherosclerosis (1). In particular, studies in RAGE Ϫ/Ϫ mice that carry the dominant-negative form of the receptor (2-6) and in RAGE-overexpressing mice (7) have confirmed an important role of RAGE activation in the development of diabetic nephropathy, neuropathy, and impaired angiogenesis. RAGE activation has also been implicated in the acceleration of atherosclerotic lesion formation as well as in the maintenance of proinflammatory and prothrombotic mechanisms, characteristic of diabetes-accelerated atherosclerosis (8,9). RAGE also represents an important mediator of oxidative stress in diabetes. Activation of RAGE in vitro leads to increased NADPH oxidase expression, mitochondrial oxidase activity, and downregulation of endogenous antioxidant activity (10,11). RAGE Ϫ/Ϫ mice have a suppression of neointimal proliferation after externally...

First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols.1 There are 2 LXR receptors encoded by distinct genes: LXRα is most highly expressed in the liver, adipose, kidney, adrenal tissues and macrophages, and LXRβ is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development.2 In this minireview we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis.