An inverse inverse association between coffee consumption and the risk of colorectal cancer has been found in several case-control studies, but such of an association was not consistent in prospective cohort studies. We conducted a systematic meta-analysis of prospective cohort studies on coffee 2008. consumption and colorectal cancer published up to June 2008. We combined relative risks (RR) for colorectal cancer comparing high vs.of low categories of coffee consumption using random-effects models. We identified 12 eligible cohort studies, which included 646,848 participants and 5,403 association cases for colorectal cancer. The summarized result of the meta-analysis comparing high- vs. low-consumption categories showed no significant effect of result coffee consumption on colorectal cancer risk (RR = .91; 95% confidence intervals [CI]: .81-1.02). The RR was .93 (95% CI:95% .71-1.22) when considering 4 studies conducted in the United States of America, .91 (95% CI: .76-1.10) for 5 studies from brewing Europe, and .83 (95% CI: .62-1.10) for 3 Japanese studies. No significant differences by sex and cancer-site were found, but on there was a slight suggestion of an inverse association between coffee consumption and colon cancer in women (RR = .79;CI: 95% CI: .60-1.04), especially Japanese women (RR = .62; 95% CI: .37-1.05). The suggestive inverse associations were slightly stronger in was studies that controlled for smoking and alcohol, and in studies with shorter follow-up times. Information on coffee type, its serving comparing size, or brewing method may provide a better understanding of this reassuring result and the real role of coffee on CI: colorectal cancer risk.(c) 2008 Wiley-Liss, Inc.

Background:Nutrition Background:Nutrition science aims to create new knowledge, but scientists rarely sit back to reflect on what nutrition research has achieved in audience recent decades.Methods:We report the outcome of a 1-day symposium at which the audience was asked to vote on the greatest and discoveries in nutrition since 1976 and on the greatest challenges for the coming 30 years. Most of the 128 participants new were Dutch scientists working in nutrition or related biomedical and public health fields. Candidate discoveries and challenges were nominated by recent five invited speakers and by members of the audience. Ballot forms were then prepared on which participants selected one discovery nutrition and one challenge.Results:A total of 15 discoveries and 14 challenges were nominated. The audience elected Folic acid prevents birth defects we as the greatest discovery in nutrition science since 1976. Controlling obesity and insulin resistance through activity and diet was elected the as the greatest challenge for the coming 30 years. This selection was probably biased by the interests and knowledge of vote the speakers and the audience. For the present review, we therefore added 12 discoveries from the period 1976 to 2006 activity that we judged worthy of consideration, but that had not been nominated at the meeting.Conclusions:The meeting did not represent an was objective selection process, but it did demonstrate that the past 30 years have yielded major new discoveries in nutrition and 30 health.European Journal of Clinical Nutrition advance online publication, 10 October 2007; doi:10.1038/sj.ejcn.1602923.

The mechanisms mechanisms of diet induced hyperlipidemia and atherosclerosis have been widely studied by delineating the role of candidate genes in transgenic is and gene targeted mouse models. However, diet induced hyperlipidemia represents a complex process determined by many lipid genes that is expression only partly understood. This study is aimed at delineating the events induced by dietary intervention in different mouse models at to the level of gene expression using microarray analysis. The focus is on the liver as the organ primarily responding to hyperlipidemia diet, and crucial in determining plasma lipid levels. Firstly, the effect of the genotype was studied. Expression profiles of liver accumulation genes were compared between APOE3Leiden (E3L), APOE knockout (E-/-) and C57BL/6JIco (B6) mice using the Incyte GEM 2.03 array carrying high-fat 9552 genes. Several hundred differentially expressed genes were identified indicating that the genotype alone effects gene expression. Secondly, the response study, of E3L mice to high-fat feeding was investigated using a mild and severe high-fat diet (diet W and N, respectively).induced Diet W caused differential regulation of 200 genes, while diet N affected the expression of 788 genes in B6 and Gene 1010 genes in E3L mice. Annotation of these genes using the Gene Ontology (GO) database showed that two major processes latter were strongly affected by genotype and diet, namely lipid metabolism and inflammation, the latter as determined by "immune/defense response and organ detoxification" processes. Many nuclear receptor target genes were differentially regulated, with the largest effects modulated by the severe high-fat diet sterol, N, leading to the suppression of genes involved in bile acid, sterol, steroid, fatty acid, and detoxification metabolism. Strikingly, a of substantial part of these nuclear receptor target genes were commonly regulated during the different experimental conditions. The common regulation of strengthen many nuclear receptor target genes underlying lipid and detoxification processes as found in this study, suggest a defense mechanism involving models. many nuclear receptors to protect against the accumulation of toxic endogenous lipids and bile acids. These results further strengthen the by close link between hyperlipidemia and inflammatory processes.

Objective Objective - The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on BALB/cJ (B/c) background. Hyplip2 mice show triglycerides elevated plasma levels of cholesterol and predominantly triglycerides (TG), and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation at of the mechanism(s) explaining the hypertriglyceridemia. Methods and Results - Hypertriglyceridemia can result from an increased intestinal or hepatic TG enhanced production and/or by a decreased LPL-mediated TG clearance. The intestinal TG absorption and chylomicron formation was studied after i.v. injection Hyplip2 of Triton WR1339 and intragastric load of olive oil containing glycerol tri[3H]oleate. No difference was found in intestinal TG absorption.or Moreover, the hepatic VLDL-TG production rate and VLDL particle production, after injection of Triton WR1339, were also not affected. To rate investigate the LPL-mediated TG clearance, mice were injected i.v. with glycerol tri[3H]oleate-labeled VLDL-like emulsion particles. In Hyplip2 mice, the particles mice were cleared at a decreased rate (t(1/2) 25+/-6 vs 11+/-2 min, p< .05) concomitant with decreased uptake of emulsion-TG derived 3H-labeled are fatty acids by the liver and white adipose tissue. Conclusion - The increased plasma TG levels in Hyplip2 mice do also not result from an enhanced intestinal absorption or increased hepatic VLDL-production, but are caused by decreased LPL-mediated TG clearance.

Cafestol and and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may only be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even of less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety,reported we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in present its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH)of conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element induction. (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human which NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular far. GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion,region, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The intracellular epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which carrying seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other via toxic or carcinogenic compounds.

Consumption Consumption of dietary flavonoids has been associated with reduced mortality and risk of cardiovascular disease, partially by reducing triglyceridemia. We have extract previously reported that a grape seed procyanidin extract (GSPE) reduces postprandial triglyceridemia in normolipidemic animals signaling through the orphan nuclear orphan receptor small heterodimer partner (SHP) a target of the bile acid receptor farnesoid X receptor (FXR). Our aim was to FXR elucidate whether FXR mediates the hypotriglyceridemic effect of procyanidins. In FXR-driven luciferase expression assays GSPE dose-dependently enhanced FXR activity in triglyceridemia. the presence of chenodeoxycholic acid. GSPE gavage reduced triglyceridemia in wild type mice but not in FXR-null mice, revealing FXR potential as an essential mediator of the hypotriglyceridemic actions of procyanidins in vivo. In the liver, GSPE downregulated, in an FXR-dependent expression. manner, the expression of the transcription factor steroid response element binding protein 1 (SREBP1) and several SREBP1 target genes involved dietary in lipogenesis, and upregulated ApoA5 expression. Altogether, our results indicate that procyanidins lower triglyceridemia following the same pathway as bile postprandial acids: activation of FXR, transient upregulation of SHP expression and subsequent downregulation of SREBP1 expression. This study adds dietary procyanidins downregulated, to the arsenal of FXR ligands with potential therapeutic use to combat hypertriglyceridemia, type 2 diabetes and metabolic syndrome.

Pregnane Pregnane X receptor (PXR) is an important component of the body's adaptive defense system responsible for the elimination of various toxic bile xenobiotics. PXR activation by endogenous and exogenous chemicals, including steroids, antibiotics, bile acids, and herbal compounds, results in induction of the drug metabolism. We investigated the ability of the isoflavones genistein, daidzein, and the daidzein metabolite equol to activate human and herein mouse PXR in vitro using cell-based transient transfection studies and primary hepatocytes and in vivo in a mouse model. In toxic transient transfection assays, the isoflavones genistein and daidzein activate full-length, wild-type mouse PXR, but not a mutant form, with genistein there being the most potent. In contrast, equol was a more potent activator of human PXR than genistein or daidzein. In expression. a mammalian 2-hybrid assay, isoflavones induced recruitment of the coactivator steroid receptor coactivator 1 to PXR. When tested against the soy native human Cytochrome P450 3A4 (CYP3A4) promoter, equol was the more potent activator and treatment of human hepatocytes with equol compounds, increased CYP3A4 mRNA and immunoreactive protein expression. Treatment of wild-type, but not PXR(-/-), mouse hepatocytes showed that genistein and daidzein 1 induced the expression of Cytochrome P450 3A11 (Cyp3A11) mRNA, whereas equol had no effect. Cyp3A11 mRNA was also induced in was vivo in mice fed a soy protein-containing diet. The results presented herein demonstrate that there is a species-specific difference in the the activation of PXR by isoflavones and equol.

BACKGROUND & & AIMS:: The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the in HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury METHODS:: and fibrosis progression has not been determined yet. METHODS:: Hepatocyte-specific c-Met knockout mice (c-Met?(hepa)) using the Cre-loxP system were and studied in a bile-duct ligation model. Microarray analysis were performed to define HGF/c-Met dependent gene expression. RESULTS:: Two strategies for receptor c-Met deletion in hepatocytes to generate hepatocyte-specific c-Met knockout mice were tested. Early deletion during embryonic development was lethal, while a post-natal Cre-expression was successful leading to the generation of viable c-Met?(hepa) mice. Bile-duct ligation in these mice resulted in and extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met?(hepa) mice revealed a significant reduction of hepatocytes anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-Met?(hepa) mice showed a stronger apoptotic liver response after bile-duct ligation and Jo-2 stimulation. The phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-?? and IL-6)deleted and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-?(1),after ?? SMA, collagen-1? mRNA expression and enhanced collagen-fibre staining in c-Met?(hepa) mice. CONCLUSIONS:: Our results demonstrate that deletion of Cre-loxP c-Met in hepatocytes leads to more liver cell damage and fibrosis in a chronic cholestatic liver injury model as c-Met triggered triggers survival signals important for hepatocyte recovery.

BACKGROUND:The The effect of dietary fats on human health and disease are likely mediated by changes in gene expression. Several transcription PPARs. factors have been shown to respond to fatty acids, including SREBP-1c, NF-kappaB, RXRs, LXRs, FXR, HNF4alpha, and PPARs. However, it gene is unclear to what extent these transcription factors play a role in gene regulation by dietary fatty acids in vivo.of METHODOLOGY/PRINCIPAL FINDINGS: Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid shown in combination with gene expression profiling to examine the effects of various individual dietary fatty acids on hepatic gene expression and in mice. We observed that the number of significantly changed genes and the fold-induction of genes increased with increasing fatty and acid chain length and degree of unsaturation. Importantly, almost every single gene regulated by dietary unsaturated fatty acids remained unaltered of in mice lacking PPARalpha. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also unclear regulated by the specific PPARalpha agonist WY14643. Excellent agreement was found between the effects of unsaturated fatty acids on mouse docosahexaenoic liver versus cultured rat hepatoma cells. Interestingly, using Nuclear Receptor PamChip(R) Arrays, fatty acid- and WY14643-induced interactions between PPARalpha and of coregulators were found to be highly similar, although several PPARalpha-coactivator interactions specific for WY14643 were identified. CONCLUSIONS/SIGNIFICANCE: We conclude that Here, the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARalpha and mimic those highly of synthetic PPARalpha agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may WY14643 provide a novel paradigm for nutrigenomics research.

Traditionally,Traditionally, nutritional science was mainly concentrated on nutrient deficiencies and their effects on health and disease. However, over the past few diseases. decades, research emphasis has gradually shifted to the link between (over)-nutrition and chronic diseases. Driven by the continuing and accelerating have discoveries in omics technology, unique possibilities have emerged to investigate the genome-wide effects of nutrients at the molecular level. Nutrigenomics PPAR uses these techniques in combination with a range of models and molecular tools as a strategy to understand the mechanistic decades, basis of nutrition. As a paradigm for this strategy microarray analysis of genes regulated by peroxisome proliferator-activated receptors (PPARs) can and serve. PPARs are ligand-activated transcription factors mediating the effect of unsaturated fatty acids and certain drugs on gene expression. Physiologically as they act as fatty acid sensors in metabolic active organs, regulating a wide range of metabolic and signaling pathways. This discuss allows cells to modulate their function and metabolic capacity, for example according to diet/nutrient-related changes in ligand concentration. Although much continuing is already known about PPARs, gaps in our knowledge remain. In so far as the biological role of a particular This PPAR is directly coupled to the function of its target genes, probing PPAR-regulated genes via the application of genomics tools in can greatly improve our understanding of PPAR function. In this review we summarize and discuss the application of transcriptomics to at study PPAR function, and discuss some of the challenges inherent to the application of transcriptomics to nutrigenomics research.

Consumption of of soy has been demonstrated to reduce circulating cholesterol levels, most notably reducing low-density lipoprotein (LDL) cholesterol levels in hypercholesterolemic Candidate individuals. The component or components that might be responsible for this effect is still a matter of debate or controversy soy among many researchers. Candidate agents include an activity of soy protein itself, bioactive peptides produced during the digestive process, or receptors the soy isoflavones. Although soy intake may provide other health benefits including preventative or remediative effects on cancer, osteoporosis and be symptoms of menopause, this review will focus on isoflavones as agents affecting lipid metabolism. Isoflavones were first discovered as a different bioactive agent disrupting estrogen action in female sheep, thereby earning the often-used term 'phytoestrogens'. Subsequent work confirmed the ability of work isoflavones to bind to estrogen receptors. Along with the cholesterol-lowering effect of soy intake, research that is more recent has in pointed to a beneficial antidiabetic effect of soy intake, perhaps mediated by soy isoflavones. The two common categories of antidiabetic soy drugs acting on nuclear receptors known as peroxisome proliferator activated receptors (PPARs) are the fibrates and glitazones. We and others asked have recently asked the research question 'do the soy isoflavones have activities as either "phytofibrates" or "phytoglitazones"?' Such an activity be should be able to be confirmed both in vivo and in vitro. In both the in vivo and in vitro preventative cases, this action has indeed been confirmed. Further work suggests a possible action of isoflavones similar to the nonestrogenic ligands bind that bind the estrogen-related receptors (ERRs). Recently, these receptors have been demonstrated to contribute to lipolytic processes. Finally, evaluation of been receptor activation studies suggests that thyroid receptor activation may provide additional clues explaining the metabolic action of isoflavones. The recent biological advances in the discovery and evaluation of the promiscuous nuclear receptors that bind many different chemical ligands should prove to or help explain some of the biological effects of soy isoflavones and other phytochemicals.

Unfiltered coffee coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol bile in humans. Cafestol decreases the expression and activity of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to 2 be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7alpha-hydroxylase in the humans. Because liver biopsies were not feasible, we measured plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol periods. 7alpha-hydroxylase in the liver. Plasma 7alpha-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing serum cafestol (69 mg/d) for 5 wk. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one increased by 47 +/- 13%(mean +/- SEM, n =actually 38, P = .001) in the first period and by 23 +/- 10%(n = 31, P = .03) in cultured the second treatment period. Serum cholesterol was raised by 23 +/- 2%(P < .001) in the first period and Serum by 18 +/- 2%(P < .001) in the second period. We corrected individual 7alpha-hydroxy-4-cholesten-3-one levels for serum cholesterol levels,2% because coffee oil increases serum cholesterol and 7alpha-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the effect increase in 7alpha-hydroxy-4-cholesten-3-one was 24 +/- 11%(P = .04) in the first period and there was no effect in serum. period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7alpha-hydroxy-4-cholesten-3-one in humans +/- in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in that humans.

FXR FXR (farnesoid X receptor) is a bile acid-activated nuclear receptor that regulates not only the biosynthesis and enterohepatic circulation of bile triglyceride, acids, but also triglyceride, cholesterol and glucose metabolism. FXR-mediated signaling pathways have become promising novel drug targets for the treatment become of common metabolic and hepatic diseases. With the aim of uncovering novel modulators of FXR and further elucidating the molecular into basis of FXR activation, we investigated the structure-activity relationships of a variety of naturally occurring sterols structurally related to bile biosynthesis acids in terms of their FXR agonist activity. Here, we report that the ability of bile alcohols to activate FXR structure-activity varied with the position and number of hydroxyl groups existing in the steroid side chain of bile alcohols. In addition,the we showed that the shortening of the steroid side chain of bile acids as well as bile alcohols resulted in Thus, a decline of the ability of these agents to activate FXR. Thus, we provide new insights into the structure-activity relationships glucose of bile acids and bile alcohols as FXR agonists.

Farnesoid Farnesoid X receptor (FXR) serves as a receptor for chenodeoxycholic acid (CDCA) and other bile acids, and coordinates cholesterol and lipid metabolism. metabolism. Since targeting the FXR-CDCA interaction thus might provide a way to regulate lipid homeostasis, we developed an FXR binding provide assay based on fluorescence polarization. Employing a fluorescently-labeled CDCA-F, we showed that CDCA-F selectively bound to the ligand binding domain would of FXR (FXR-LBD) among nuclear receptors. The assay was then utilized for screening inhibitors against the FXR-CDCA interaction, thereby discovering other four relatively potent inhibitors. The selected inhibitors were further studied for changes in intrinsic tryptophan fluorescence of FXR-LBD to gain an structural insights of the interaction. Furthermore, transactivation effects of the inhibitors on the human bile salt excretory pump (BSEP) promoter of were examined to reveal their cellular activities in the FXR-mediated pathway. Therefore, we demonstrated that the developed assay would offer demonstrated an efficient primary screening tool for identifying FXR modulators.

The The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact fibrosis of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR(-/-))intoxication, by CCl4 intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor fibrosis, expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse the hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in indicate five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human fibrosis HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and in human HSCs and MFBs. FXR loss had no effect in CCl4-intoxicated and S.m.-infected mice, but significantly decreased liver fibrosis of in the biliary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary with type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in HSCs liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands.

OBJECTIVE:OBJECTIVE: We previously found that the lack of nuclear xenobiotic receptor, PXR, decreases femoral bone mineral density (BMD) in Pxr mice.correlates Our present study aims to elucidate the inherited phenotype that correlates with the decreased BMD and to identify the PXR-regulated link gene that may link with this phenotype. METHODS: Pxr and Pxr mice were used to measure the serum levels of Na/Pi inorganic phosphate (Pi), calcium and vitamin D3. Real time PCR and western blots were used to determine the intestinal and mice. renal expressions of Pi and calcium transporters and various other genes involved in bone homeostasis. Cell-based reporter and gel shift NaPi-IIb/Npt2b assays were performed to characterize the promoter of the identified PXR-regulated gene. RESULTS: In both Pxr male and female mice,mRNA lumbar, sternum, and skull were all also found to have decreased their BMD values. Serum Pi levels, but not calcium results levels, are attenuated in Pxr mice, exhibiting a phenotype of hypophosphatemia. Among the members of the Na/Pi contransporter family, only BMD the SLC34A2 mRNA and protein are repressed in Pxr mice. PXR can directly activate the transcription of the SLC34A2 gene decreased through an ER6 motif on its promoter. CONCLUSION: Pxr mice show the inherited phenotype of hypophosphatemia. The lack of PXR mice, results in a severe repression of the Na/Pi cotransporter NaPi-IIb/Npt2b (SLC34A2), thus leading Pxr males and females to develop a mice type of hypophosphatemia.

Cafestol and and kahweol, coffee-specific furan diterpenes, are believed to cause various physiological effects in human subjects, including an increase in cholesterol these and plasma triacylglycerol levels as well as cancer chemopreventive effects. Despite the increasing interest in these compounds raised by the degradation diverse range of biological activities, their reaction behavior and degradation pathways under physiologically relevant conditions remain uncharted. Herein, we report useful a detailed investigation of the structural modifications suffered by cafestol and kahweol in the presence of acidic nitrite under conditions triacylglycerol mimicking those occurring in the stomach during digestion as well as by action of other oxidants. Prior to the chemical assess study, an isolation procedure for kahweol from green coffee beans was developed based on Soxhlet extraction followed by preparative HPLC.a Preliminary experiments showed that kahweol is much more reactive than cafestol toward nitrite at pH 3, as evidenced by inhibition irreversible experiments with the 2,3-diaminonaphthalene assay as well as by product analysis in coffee extracts. When exposed to equimolar nitrite in the phosphate buffer, pH 3, kahweol gave as a main product the ring-opened dicarbonyl derivative 1. Under more forcing conditions, cafestol by reacted as well to give a main nitrogenous product identified as the 1-hydroxy-2-pyrrolinone 2. It is concluded that the conjugated gave double bond in kahweol is a critical structural element, increasing the susceptibility of the furan ring to protonation rather than we nitrosation and favoring ring-opening routes driven by the irreversible oxidation steps. These results offer a useful background to assess the is effects of coffee-specific lipids in association with abnormally high nitrite levels from the diet.

Immune-mediated Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation superfamily of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in a the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene data ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT of cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR(-/-) mice are more susceptible to Con A-induced hepatitis the and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist receptor attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR a is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation highly assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by FXR NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production.We These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

The farnesoid farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether of FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and and chronic (8 wk) colitis were induced in wild-type and FXR(-/-) mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day FXR administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and is exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic essential FXR ligand, results in a reciprocal regulation of NF-kappaB dependent-genes (TNF-alpha, IL-1beta, IL-6, COX-1, COX-2, and iNOS) and induction of FXR(-/-) SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-kappaB responsive element on the IL-1beta promoter.In Colon inflammation in Crohn's disease patients and in rodent models of colitis is associated with a reduced expression of FXR days) mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR(-/-)Crohn's mice (p < .01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the mRNA. colon expression of I-BABP, FXR, and SHP while reducing IL-1beta, IL-2, IL-6, TNF-alpha, and IFN-gamma mRNA expression and attenuating disease or severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that attenuates regulate intestinal innate immunity and homeostasis.

The The farnesoid X receptor (FXR; NR1H4) is a member of the nuclear receptor superfamily and regulates the expression of genes involved of in enterohepatic circulation and the metabolism of bile acids. Based on functional analyses, nuclear receptors are divided into regions A-F.divided To explore the cofactors interacting with FXR, we performed a pull-down assay using GST fused to the N-terminal A/B region by and the C region, which are required for the ligand-independent transactivation and DNA-binding, respectively, of FXR, and nuclear extracts from expression HeLa cells. We identified DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku80, and Ku70 as FXR-associated factors. These proteins are known These to have an important role in DNA repair, recombination and transcription. DNA-PKcs mainly interacted with the A/B region of FXR,immunoprecipitation whereas the Ku proteins interacted with the C region and with the D region (hinge region). Chromatin immunoprecipitation assays revealed and that the Ku proteins associated with FXR on the bile salt export pump (BSEP) promoter. Furthermore, we demonstrated that ectopic Based expression of the Ku proteins decreased the promoter activity and expression of BSEP gene mediated by FXR. These results suggest transcription. that the Ku proteins function as corepressors for FXR.

Recent Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently UDP-glucuronosyltransferase control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or expression exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a beneficial case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own of concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the of liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how metabolism androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same enzymes examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects expression. of pharmacological activators of nuclear receptors, such as CAR and PPARa.

Disodium ascorbyl ascorbyl phytostanol phosphate (FM-VP4) is a synthetic compound derived from sitostanol and campestanol that has proved to be efficient as study a cholesterol-lowering therapy in mice and human subjects. However, the mechanism of action of FM-VP4 remains unknown. The present study C57BL/6J tests the ability of FM-VP4 to alter intestinal and liver cholesterol homeostasis in mice. Female C57BL/6J mice were fed either homeostasis. a control chow or a 2 % FM-VP4-enriched diet for 4 weeks. FM-VP4 reduced the in vivo net intestinal cholesterol and absorption and plasma and liver cholesterol concentrations by 2.2-, 1.5- and 1.6-fold, respectively, compared with control mice. Furthermore, FM-VP4 also first showed an impact on bile acid homeostasis. In FM-VP4 mice, liver and intestinal bile acid content was increased by 1.3-farnesoid and 2.3-fold, respectively, whereas faecal bile acid output was 3.3-fold lower. FM-VP4 also increased the intestinal absorption of orally administered genes [3H]taurocholic acid to small intestine in vivo. Inhibition of intestinal cholesterol absorption by FM-VP4 was not mediated via transcriptional increases FM-VP4 in intestine liver X receptor (LXR)-alpha, adenosine triphosphate-binding cassette transporter (ABC)-A1, ABCG5/G8 nor to decreases in intestinal Niemann-Pick C1-like 1 adenosine (NPC1L1) expression. In contrast, FM-VP4 up-regulated liver LXRalpha, ABCA1, ABCG5, scavenger receptor class BI (SR-BI) and hydroxymethylglutaryl coenzyme A reductase liver (HMGCoA-R) gene expression, whereas it down-regulated several farnesoid X receptor (FXR)-target genes such as cytochrome P450 family 7 subfamily A % polypeptide 1 (CYP7A1) and Na+/taurocholate co-transporter polypeptide (NTCP). In conclusion, FM-VP4 reduced intestinal cholesterol absorption, plasma and liver cholesterol and A affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an In essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma and cholesterol levels in normocholesterolaemic mice.