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)

Polyunsaturated fatty acids (PUFAs) have been previously reported as agonists of peroxisome proliferatoractivated receptor and antagonists of the liver X receptor. The activities on these two nuclear receptors have been attributed to their beneficial effects such as improvement of dyslipidemia and insulin sensitivity and decrease of hepatic lipogenesis. Here we report that PUFAs are ligands of farnesoid X receptor (FXR), a nuclear receptor for bile acids. In a conventional FXR binding assay, arachidonic acid (AA, 20:4), docosahexaenoic acid (DA, 22:6), and linolenic acid (LA, 18:3) had an affinity of 2.6, 1.5, and 3.5 microM, respectively. In a cell-free coactivator association assay, AA, DA, and LA decreased FXR agonist-induced FXR activation with IC(50)s ranging from 0.9 to 4.7 microM. In HepG2 cells, PUFAs regulated the expression of two FXR targets, BSEP and kininogen, in an opposite fashion, although both genes were transactivated by FXR. All three PUFAs dose-dependently enhanced FXR agonist-induced BSEP expression but decreased FXR agonist-induced human kininogen mRNA. Saturated fatty acids such as stearic acid (SA, 18:0) and palmitic acid (PA, 16:0) did not bind to FXR and did not change BSEP or kininogen expression. The pattern of BSEP and kininogen regulation by PUFAs is closely similar to that of the guggulsterone, previously reported as a selective bile acid receptor modulator. Our results suggest that PUFAs may belong to the same class of FXR ligands as guggulsterone, and that the selective regulation of FXR targets may contribute to the beneficial effects of PUFAs in lipid metabolism.
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PMID:Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. 1530 55

Guggulsterone (GS) is the active substance in guggulipid, an extract of the guggul tree, Commiphora mukul, used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation. The activity of GS has been suggested to be mediated by antagonism of the receptor for bile acids, the farnesoid X receptor (FXR). Here, we demonstrate that both stereoisomers of the plant sterol, (E)- and (Z)-GS, bind to the steroid receptors at a much higher affinity than to FXR. Both stereoisomers bind to the mineralocorticoid receptor (MR) with a Ki value of approximately 35 nM, which is greater than 100 times more potent than their affinity for FXR. Both (E)- and (Z)-GS also displayed high affinity for other steroid receptors, including the androgen (AR), glucocorticoid (GR), and progesterone receptors (PR) with Ki values ranging from 224 to 315 nM. In cell-based functional cotransfection assays, GSs behaved as antagonists of AR, GR, and MR, but as agonists of PR. Agonist activity was also demonstrated with estrogen receptor (ER) alpha; however, the potency was very low (EC50 > 5000 nM). In addition, GS displayed activity in functional assays in cell lines expressing endogenous AR, GR, ER, and PR. These data suggest that the variety of pharmacological effects exhibited by GS may be mediated by targeting several steroid receptors.
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PMID:The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. 1560 4

Dyslipidemia and gallbladder diseases are two current anomalies observed in patients suffering from the metabolic syndrome and type 2 diabetes. The bile acid-activated nuclear receptor farnesoid X receptor (FXR) controls bile acid as well as lipid metabolism. Recent observations indicate a role for FXR also in carbohydrate metabolism. Hepatic FXR expression is altered in diabetic animal models in vivo and regulated by hormones and nutrients in vitro. At the molecular level, FXR activation modifies the transcriptional activity of different transcription factors controlling gluconeogenesis and lipogenesis, thus affecting in concert bile acid, lipid and carbohydrate metabolism. The present review focuses on recent advances in our understanding of the modulation of carbohydrate metabolism by FXR. These observations raise the intriguing possibility for a modulatory role of this receptor also in the metabolic syndrome.
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PMID:Potential regulatory role of the farnesoid X receptor in the metabolic syndrome. 1573 43

The farnesoid X receptor (FXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidemia and cholestasis. Hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent FXR activators originated from natural product-like libraries. A training set containing 82 compounds served to establish the models. The best HQSAR model was generated using atoms, bonds, connections, chirality, and donor and acceptor as fragment distinction and fragment size default (4-7) with six components. The model was used to predict the potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results. The final HQSAR model and the information obtained from HQSAR 2D contribution maps should be useful for the design of novel FXR ligands having improved potency.
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PMID:Hologram quantitative structure-activity relationships for a series of farnesoid X receptor activators. 1589 27

Lipids are essential components of biological membranes, fuel molecules and metabolic regulators that control cellular functions, metabolism and homeostasis. The liver plays a central role in regulating lipid metabolism and whole body lipid homeostasis. Sterols, bile acids and fatty acids are the endogenous ligands of the liver orphan receptor, farnesoid X receptor, peroxisome proliferator-activated receptor, vitamin D receptor, constitutive androstane receptor and pregnane X receptor. These metabolic receptors coordinately regulate lipid, glucose, energy and drug metabolism. Alteration of lipid homeostasis causes dyslipidemia, which is a major risk factor contributing to atherosclerotic cardiovascular diseases, diabetes, obesity and liver diseases. Advances in the understanding of the mechanisms of nuclear receptor regulation of lipid homeostasis have provided an opportunity to investigate potential therapeutic drugs targeted to nuclear receptors. This could be useful for the treatment of diabetes, and cardiovascular and chronic liver diseases.
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PMID:Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases. 1625 20

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

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

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

The metabolic syndrome is a cluster of metabolic disorders, such as abdominal obesity, dyslipidemia, hypertension and impaired fasting glucose that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated and the precise mechanisms have not been elucidated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. This review explores the physiological functions and molecular actions of bioactive lipids, such as n-3 polyunsaturated fatty acids, conjugated fatty acids, sterols, medium-chain fatty acids, diacylglycerols and phospholipids, in the development of metabolic syndrome. Dietary bioactive lipids suppress the accumulation of abdominal adipose tissue and lipids in the liver and serum, and alleviate hypertension and type 2 diabetes through the transcriptional regulation of lipid and glucose metabolism. Peroxisome proliferator-activated receptors (PPARs), sterol regulatory element binding proteins, liver X receptor alpha, retinoid X receptor alpha, farnesoid X receptor alpha, hepatic nuclear factor 4alpha and nuclear factor kappaB contribute to these nuclear actions of bioactive lipids with complex interactions. Recent studies have demonstrated the striking ability of bioactive lipids to regulate the production of physiologically active adipocytokines through PPARgamma activation. In particular, the function of bioactive lipids as dietary adiponectin inducers (dietary insulin sensitizers) deserves attention with respect to alleviation of metabolic syndrome by dietary manipulation.
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PMID:Bioactive lipids in metabolic syndrome. 1817 44

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


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