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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear receptors represent novel targets for the development of therapeutic agents for the treatment of numerous diseases, including type 2 diabetes, obesity dyslipidemia, atherosclerosis and the metabolic syndrome. There have been many recent advances in the development of new therapeutic agents for a subset of these receptors, including the peroxisome proliferator-activated receptors, the liver X receptors and the farnesoid X receptor. To date, the synthesis of selective modulators that regulate the activity of these receptors has been empirical. However, a detailed understanding of the molecular basis for selective modulation, as well as new insights into the biology of these receptors, might open the door to the rational design of a new generation of therapeutic agents with improved safety and efficacy.
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PMID:Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. 1687 Apr 65

Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds).
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PMID:Novel agents to manage dyslipidemias and impact atherosclerosis. 1701 3

The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.
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PMID:Farnesoid X receptor agonist reduces serum asymmetric dimethylarginine levels through hepatic dimethylarginine dimethylaminohydrolase-1 gene regulation. 1706 54

The metabolic syndrome is an insulin-resistant state that is characterized by a cluster of cardiovascular risk factors, including abdominal obesity, hyperglycemia, elevated blood pressure and combined dyslipidemia. In this review, we discuss the role of the bile-acid-activated farnesoid X receptor (FXR) in the modulation of the metabolic syndrome. Owing to its regulatory actions in lipid and glucose homeostasis, FXR is a potential pharmacological target. Moreover, the observation that FXR also influences endothelial function and atherosclerosis indicates a regulatory role in the cardiovascular complications that are associated with the metabolic syndrome. The pharmacological activation of FXR leads to a complex response that integrates beneficial actions and potentially undesirable side-effects. Thus, the identification of selective FXR modulators (selective bile acid receptor modulators) is required for the development of compounds that can be used to treat the metabolic syndrome.
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PMID:FXR: a promising target for the metabolic syndrome? 1741 31

The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
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PMID:A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. 1751 56

Despite the success of existing therapies, new therapies targeted toward dyslipidemia are still needed. Liver X receptor (LXR) and farnesoid X receptor (FXR) represent 2 very different attractive targets for new therapeutic development. LXR is a nuclear receptor that primarily acts to rid cells and the body of excess cholesterol. LXR agonists have been shown to reduce atherosclerosis in animals and are therefore of great interest as a therapeutic approach. Despite some increases in hepatic fat and low-density lipoprotein (LDL) cholesterol in preclinical models, LXR remains an important new target. FXR is a nuclear receptor that primarily acts to protect hepatocytes against the effects of elevated bile acids. FXR agonists also have triglyceride-lowering properties and could be useful in treating certain types of dyslipidemia. FXR modulators or antagonists could potentially lower LDL cholesterol levels and even modulate high-density lipoprotein metabolism. FXR is a complicated but fascinating target for the development of new therapeutic approaches.
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PMID:Liver X receptor and farnesoid X receptor as therapeutic targets. 1804 47

Nuclear hormone receptors, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and the farnesoid X receptor (FXR), are transcription factors involved in the regulation of essential metabolic functions, including glucose and lipid metabolism, reverse cholesterol transport, and the regulation of bile acids. This review summarizes new developments in the use of PPAR, LXR and FXR agonists for the treatment of obesity and cardiovascular diseases, including dyslipidemia and atherosclerosis. Currently available drugs and future areas of research for new therapies are also discussed.
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PMID:Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. 1831 60

Previous epidemiological studies have demonstrated the low level of high-density lipoprotein (HDL) cholesterol as an independent risk factor for cardiovascular diseases, the increase of which is one of the cornerstones of preventive cardiovascular care. In addition to its major role in reverse cholesterol transport, HDL-C has other biological activities that may contribute to its protective effects against atherosclerosis. These include antioxidant, anti-inflammatory, antithrombotic/profibrinolytic and vasoprotective effects. Current guidelines recommend aggressive lifestyle modifications, niacin, fibrate, statin or a combination of these to increase HDL-cholesterol levels. In addition, several novel HDL-based therapeutic strategies have been or are currently being tested. These include newer formulations of nicotinic acid/receptor agonists, CETP inhibitors, cannabinoid-1 receptor antagonists, PPAR agonists, liver X receptor/farnesoid X receptor agonists, and apoA-I and/or phospholipid-derived therapies. In this article previous clinical trials, epidemiological observations, basic science studies and the most important trials of novel agents are reviewed.
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PMID:[New trends in lipidology: the increasing role of HDL-cholesterol]. 1862 98

The liver plays a central role in the regulation of cholesterol homeostasis. Hepatic cholesterol content is maintained by a complex interplay between input and output pathways; alterations in the balance among these processes may lead to accumulation of excess cholesterol in body compartments with potentially deleterious consequences at the level of blood vessels (atherosclerosis) and biliary tract (gallstone disease). Molecular biology has brought new insights into this field. Nuclear receptors have been shown to play a key role in the "sensing" of intracellular cholesterol levels and in the triggering of metabolic responses via the sterol regulatory element binding protein (SREBP) cascade. A nuclear receptor for bile acids, farnesoid X receptor (FXR), has been identified and the molecular pathways underlying feedback inhibition of bile acid synthesis, the main mechanism of irreversible degradation of cholesterol, have been clarified. Such regulation involves a number of additional coactivators/corepressors of the transcription of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase. Finally, the main transporters of biliary lipids (bile acids, phospholipids and cholesterol) have been described; most of them undergo transcriptional control by nuclear receptors, allowing regulation of biliary lipid efflux in conditions of different intracellular availability. Despite a body of evidence coming from experimental models the intimate mechanisms of regulation have not been clearly defined and direct evidence in humans is rather limited. This review will focus on the role of nuclear receptors in the regulation of hepatic cholesterol degradation and biliary lipid secretion, and on the theoretical applications from a pharmacotherapeutic perspective.
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PMID:Nuclear receptors as potential molecular targets in cholesterol accumulation conditions: insights from evidence on hepatic cholesterol degradation and gallstone disease in humans. 1878 49

Multiple studies suggest increased conversion of cholesterol to bile acids by cholesterol 7alpha-hydroxylase (CYP7A1) protects against dyslipidemia and atherosclerosis. CYP7A1 expression is repressed by the sequential activity of two nuclear hormone receptors, farnesoid X receptor (FXR) and small heterodimer partner (SHP). Here we demonstrate 129 strain SHP(-/-) mice are protected against hypercholesterolemia resulting from either a cholesterol/cholic acid (chol/CA) diet or from hypothyroidism. In a mixed 129-C57Bl/6 background, LDLR(-/-) and LDLR(-/-)SHP(-/-) mice had nearly identical elevations in hepatic cholesterol content and repression of cholesterol regulated genes when fed a Western diet. However, the LDLR(-/-)SHP(-/-) mice had greatly reduced elevations in serum VLDL and LDL cholesterol levels and triglyceride (TG) levels as compared with LDLR(-/-) mice. Additionally, the hepatic inflammation produced by the Western diet in the LDLR(-/-) mice was abolished in the LDLR(-/-)SHP(-/-) mice. CYP7A1 expression was induced 10-fold by the Western diet in the LDLR(-/-)SHP(-/-) mice but not in the LDLR(-/-) mice. Finally, hepatocyte-specific deletion of SHP expression was also protective against dyslipidemia induced by either a chol/CA diet or by hypothyroidism. While no antagonist ligands have yet been identified for SHP, these results suggest selective inhibition of hepatic SHP expression may provide protection against dyslipidemia.
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PMID:Loss of small heterodimer partner expression in the liver protects against dyslipidemia. 1882 Feb 41


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