Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0242339 (dyslipidemia)
13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (alpha, gamma, and sigma) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.
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PMID:Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders. 1856 91

The nuclear receptor PPARs (peroxisomal proliferators-activated receptors) are transcription factors activated by natural and synthetic ligands. Three different isoforms of PPARs have been described, PPARalpha, PPARbeta/ delta, and PPARgamma. PPARs isoforms are tissue-dependent expressed and they regulate the gene expression of proteins involved in glucose and lipid metabolism. Selective pharmacological activation of these isoforms has revealed their role in cellular physiology. Nowadays, two kinds of PPARs agonists are currently used in the clinical practice, the fibrate hypolipidemic drugs, used in the treatment of dyslipidemia, are synthetic ligands for PPARalpha, whereas thiazolidinediones or glitazones have PPARgamma selectivity and are used as hypoglycemic agents. The main cellular effect of PPAR activation lies on fatty acid oxidation and mobilization (PPARalpha) as well as they act as insulin sensitizers on peripheral tissues (PPARgamma). In addition to these beneficial effects of PPARs, it has also been demonstrated that PPARs activation can prevent cardiac dysfunction in diabetic patients as well as the anti-inflammatory processes developed in many diseases. Recent development of PPARbeta/delta and hybrid PPARs alpha and gamma agonists, and their clinical trials are giving promising outcomes in the therapeutics of metabolic syndrome, diabetes and cardiac diseases.
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PMID:[PPARs, metabolic syndrome and cardiac diseases]. 1893 1

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARalpha agonist is realized.
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PMID:Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo. 1897 26

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient (FXR(-/-)) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR(-/-) mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
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PMID:Role of bile acids and bile acid receptors in metabolic regulation. 1912 57

The hepatocyte nuclear factor 4alpha (HNF4alpha) is a liver-enriched nuclear receptor that plays a critical role in early morphogenesis, fetal liver development, liver differentiation and metabolism. Human HNF4alpha gene mutations cause maturity on-set diabetes of the young type 1, an autosomal dominant non-insulin-dependent diabetes mellitus. HNF4alpha is an orphan nuclear receptor because of which the endogenous ligand has not been firmly identified. The trans-activating activity of HNF4alpha is enhanced by interacting with co-activators and inhibited by corepressors. Recent studies have revealed that HNF4alpha plays a central role in regulation of bile acid metabolism in the liver. Bile acids are required for biliary excretion of cholesterol and metabolites, and intestinal absorption of fat, nutrients, drug and xenobiotics for transport and distribution to liver and other tissues. Bile acids are signaling molecules that activate nuclear receptors to control lipids and drug metabolism in the liver and intestine. Therefore, HNF4alpha plays a central role in coordinated regulation of bile acid and xenobiotics metabolism. Drugs that specifically activate HNF4alpha could be developed for treating metabolic diseases such as diabetes, dyslipidemia and cholestasis, as well as drug metabolism and detoxification.
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PMID:Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism. 1923 93

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor alpha. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.
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PMID:Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics. 1925 19

Metabolic syndrome, diabetes and obesity are frequently associated with hypertriglyceridemia, hypercholesterolemia and low HDL levels, a phenotype known as atherogenic dyslipidemia. Atherogenic dyslipidemia and hypertriglyceridemia are frequently treated with fibric acid derivatives which activate the nuclear receptor PPAR-alpha leading to reduce plasma triglycerides and an increase in HDL cholesterol levels. The mechanism by which activation of PPAR-alpha with fibrates improves the plasma lipid profile in patients with atherogenic dyslipidemia and hypertriglyceridemia has been examined in several small studies measuring lipoprotein kinetics. The results of these studies indicate that the changes in lipoprotein metabolism observed in response to fibrate treatment vary according to lipoprotein phenotype. In general, fibrates act to reduce VLDL apoB-100 through enhanced fractional catabolism (clearance) of VLDL apoB-100 with additional effects on reducing VLDL apoB-100 production. LDL apoB-100 levels generally decrease in response to fibrates due to increased LDL fractional catabolism except in those patients with high to very high plasma triglyceride levels (>400mg/dL). Fibrates also increase HDL apoA-I and apoA-II levels by enhancing apoA-I and apoA-II production, although this is partially counteracted by increasing fractional catabolism of these apolipoproteins. The potent and specific PPAR-alpha agonist LY518674, reduced VLDL apoB-100 levels through enhanced fractional catabolism similar to what is seen with fibrates. In contrast to fibrates, LY518674 did not change HDL apoA-I levels in response to due to an increased turnover of apoA-I where an increased fractional catabolic rate entirely counteracted the increase in apoA-I production. The changes in apoB metabolism in response to PPAR-alpha activation with fibrates and specific PPAR-alpha agonists would be expected to reduce the risk of cardiovascular disease. However, the benefit of the enhanced turnover of HDL apoA-I in response to PPAR-alpha activation remains to be determined.
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PMID:The effect of PPAR-alpha agonism on apolipoprotein metabolism in humans. 2000 15

Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics such as bile acids and drugs. Research in the last two decades provided researchers and clinicians with a detailed understanding of the regulation of these processes and, most importantly, also prompted the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases. Some nuclear receptor agonists are already used in daily clinical practice but many more are currently designed or tested for the treatment of diabetes, dyslipidemia, fatty liver disease, cancer, drug hepatotoxicity and cholestasis. The hydrophilic bile acid ursodeoxycholic acid is currently the only available drug to treat cholestasis but its efficacy is limited. Therefore, development of novel treatments represents a major goal for both pharmaceutical industry and academic researchers. Targeting nuclear receptors in cholestasis is an intriguing approach since these receptors are critically involved in regulation of bile acid homeostasis. This review will discuss the general role of nuclear receptors in regulation of transporters and other enzymes maintaining bile acid homeostasis and will review the role of individual receptors as therapeutic targets. In addition, the central role of nuclear receptors and other transcription factors such as the aryl hydrocarbon receptor (AhR) and the nuclear factor-E2-related factor (Nrf2) in mediating drug disposition and their potential therapeutic role in drug-induced liver disease will be covered.
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PMID:Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity. 2038 26

Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA-binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
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PMID:Role of nuclear receptor SHP in metabolism and cancer. 2097 Apr 97

Bile acids are not only intestinal detergents, but also act as signaling molecules to control bile acid and metabolic homeostasis. By binding to the nuclear receptor farnesoid X receptor (FXR) or the membrane receptor TGR5, bile acids regulate lipid, glucose, and energy metabolism. The removal of bile acids from the enterohepatic cycle by orally administered sequestrants, nonabsorbable resins that complex bile acids in the intestinal lumen, is an effective treatment to reduce plasma cholesterol concentrations in dyslipidemia. In diabetic patients, sequestrants further lower hyperglycemia, and are thus useful in glycemic control. Here, we review the signaling pathways involved in the glucose-regulatory function of bile acids and our current understanding of the mechanisms behind the glucose-lowering effect of bile acid sequestrants.
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PMID:Bile acid sequestrants: glucose-lowering mechanisms. 2097 65


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