Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.
 ...
PMID:Nuclear receptors and the control of metabolism. 1251 1

Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.
 ...
PMID:The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter. 1583 98

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.
 ...
PMID:Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases. 1625 20

The nuclear receptor constitutive androstane receptor (CAR), a key transcription factor for the expression of cytochrome P450 (CYP) 2B genes, resides in the cytoplasm under untreated conditions and translocates into the nucleus upon xenobiotic exposure. CAR forms a multiprotein complex including heat shock protein 90 in the cytoplasm as the glucocorticoid receptor, and it is likely that protein phosphatase 2A plays a critical role in the first step of CAR nuclear translocation. In addition to the xenobiotic induction of CYP2Bs, our recent studies have indicated that CAR is important for sex and strain differences and obesity/diabetes-associated changes in the expression of CYP2B genes. These results have raised the hypothesis that the expression of nuclear receptors varies depending on the physiologic condition, leading to the dysregulation of CYP expression. In obese mice fed a high-fat diet, however, hepatic CYP3A levels are drastically decreased without any significant changes in the expression of nuclear receptors including the pregnane X receptor and hepatocyte nuclear factor-4, which are known to be key transcription factors in the expression of CYP3A genes. These results indicate that it is important to investigate the mechanism of the transcriptional regulation of nuclear receptor genes as well as the activation of nuclear receptors to understand the CYP expression system fully.
 ...
PMID:[Roles of nuclear receptors in the gene expression of drug-metabolizing enzymes under various physiological conditions]. 1667 42

Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the peroxisome proliferators activated receptor alpha, pregnane X receptor, and estrogen receptor by DHEA and its metabolites have been demonstrated. Several membrane-associated receptors have also been elucidated leading to additional mechanisms by which DHEA may exert its biological effects. This review will provide an overview of the receptor multiplicity involved in the biological activity of this sterol.
 ...
PMID:The biological actions of dehydroepiandrosterone involves multiple receptors. 1668 50

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5 alpha-androstan-3 alpha-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
 ...
PMID:Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor. 1759 76

To investigate the pharmacokinetic characteristics in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of type 2 diabetes and obesity, the expressions of major hepatic CYP enzymes in TSOD and TSNO (Tsumura, Suzuki, non-obesity; control) mice were compared. The 7-month-old TSOD mice, which represented severe obesity/diabetes-related pathophysiology, showed higher expressions of Cyp2c and Cyp3a compared with TSNO mice, while those of Cyp1a and Cyp2e were lower. Cyp3a metabolic activity was also higher in TSOD mice. In the 7-month-old liver, pregnane X receptor (PXR) (nuclear receptor) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) (cofactor) mRNA expression were higher in TSOD mice, possibly playing a role in the altered expression of Cyp3a. This specifically altered CYP expression in TSOD mice suggests that the biotransformation of drugs metabolized by these CYP enzymes differs from that in normal animals. Based on these findings, further investigation on the relationship between altered CYP expression and pathophysiology may be useful in elucidating changes in pharmacokinetics in obese/diabetic patients.
 ...
PMID:Altered expression of CYP in TSOD mice: a model of type 2 diabetes and obesity. 1992 81

Drugs for weight loss have been in use for nearly hundred years. Orlistat (Xenical) is a non-centrally acting anti-obesity drug that inactivates gastric and intestinal lipases, thus, preventing absorption of dietary triglycerides. There are reports indicating that Orlistat reduces bioavailability of Cyclosporin to a clinically relevant degree. Since Cyclosporin is metabolized by cytochrome P450 CYP3A4, we examined whether interaction between Orlistat and Cyclosporin involves induction of CYP3A4. Human Caucasian colon adenocarcinoma cells LS174T and primary cultures of human hepatocytes were used, as in vitro models of intestinal and hepatic cells, respectively. Treatment of LS174T cells for 24h with Orlistat (1-100mg/L) did not cause induction of CYP3A4 mRNA levels as compared to control cells while Orlistat (100mg/L) slightly induced CYP3A4 mRNA in human hepatocytes. Rifampicin, a model CYP3A4 inducer, significantly induced CYP3A4 mRNA in both types of cells. The level of CYP3A4 protein in human hepatocytes was increased by Orlistat after 48h, while rifampicin strongly induced CYP3A4 protein level. In addition, Orlistat moderately dose-independently activated pregnane X receptor (PXR) in LS174T cells transiently transfected with p3A4-luc reporter construct containing the basal promoter (-362/+53) with proximal PXR response element and the distal xenobiotic responsive enhancer module (-7836/-7208) of the CYP3A4 gene 5'-flanking region. In conclusion, we report here that Orlistat is weak PXR activator and CYP3A4 inducer in human hepatocytes, but it has no effect on CYP3A4 in intestinal cells, implying no role of CYP3A4 induction in the interaction between Orlistat and Cyclosporin in absorption process.
 ...
PMID:Investigation of Orlistat effects on PXR activation and CYP3A4 expression in primary human hepatocytes and human intestinal LS174T cells. 2059 1

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two closely related and liver-enriched nuclear hormone receptors originally defined as xenobiotic receptors. PXR and CAR regulate the transcription of drug-metabolizing enzymes and transporters, which are essential in protecting our bodies from the accumulation of harmful chemicals. An increasing body of evidence suggests that PXR and CAR also have an endobiotic function that impacts energy homeostasis through the regulation of glucose and lipids metabolism. Of note and in contrast, disruptions of energy homeostasis, such as those observed in obesity and diabetes, also have a major impact on drug metabolism. This review will focus on recent progress in our understanding of the integral role of PXR and CAR in drug metabolism and energy homeostasis.
 ...
PMID:Pregnane X receptor and constitutive androstane receptor at the crossroads of drug metabolism and energy metabolism. 2073 25

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets.
 ...
PMID:Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. 2086 55


1 2 3 4 Next >>