The PCO 2 was significantly higher in group 3 compared to group 1. This is in contrast to a study where a buffer solution was instilled into a cannulated gallbladder and demonstrated a pH decrease and PCO 2 increase in normal feline bile and no alteration of pH or PCO 2 in the presence of inflammation (30). These divergent results could be attributed to the fact that the inflammation was not septic in the latter study. The increase of PCO 2 may result from the reaction between H + and bicarbonate ions, yielding CO 2 and water (31) but further studies are warranted to confirm this hypothesis. Sodium was significantly higher in group 3 compared to groups 1 and 2. There may be a net loss of free water in the bile in the presence of bacterial infection. However, this seems unlikely considering the fact that in an inflamed feline gallbladder there is a net secretion of water whereas in the normal gallbladder there is a net absorption (30). As the Na/K ratio was significantly lower in group 1 compared to group 3 in this study, an alteration in the function of the Na + -K + -ATPase pump (31) in the gallbladder wall in the presence of inflammation and/or infection is suspected. Some factors hypothesized to contribute to Na + -K + pump dysfunction include membrane damage, impaired ATP production, or impaired hormone receptors involved in transport control, such as aldosterone. Indeed, it has been demonstrated in the rabbit that aldosterone has an influence on sodium excretion in the bile (32, 33). The effect of aldosterone on bilecomposition in the cat is unknown, however this merits further investigation.
Fig. 2. CT and UDCA impact on post-EH outcome in mice. (A) CT (2%) treatment reduced post-EH liver injury (at 24 h), signi ﬁcantly in TGR5-KO mice, as shown on H&E-stained liver sections (left, representative images of n = 4 –9 mice/group, objective ×10, scale bar: 100 l m) and semi-quantitative analysis ( right histo- gram). (B) UDCA (0.5%) treatment is associated with less liver injury after EH (at 6 h) (n = 6–8 mice/group) in TGR5-KO but not WT mice; H&E-stained liver sections ( left, representative images, objective ×10) and semi-quantitative analysis (right histogram). (C) Liver BA composition (DCA and x -MCA) before and 6 h after EH in WT and TGR5-KO mice, fed with a diet enriched or not (ND) with 0.5% UDCA (n = 6 –8 mice/group). (D) Hydrophobicity index in UDCA-treated WT and TGR5-KO mice. Hydrophobicity index calculated from BA analysis in liver and bile from WT and TGR5-KO mice 6 h after EH (n = 6 –8 mice/group. (E) Choleretic effect of 0.5% UDCA-enriched diet (7 days), in WT but not TGR5-KO mice (n = 5 mice/group). * p <0.05; **p <0.01; ***p <0.001; Student’s t test. BA, bile acid; CT, cholestyramine; DCA, deo xycholic acid; EH, extended hepatectomy; KO, knockout; MCA, muricholic acid; ND, normal diet; TGR5, Takeda G protein coupled receptor; UDCA, ursodeoxycholic acid; WT, wild-type.
mice treated with a pharmacological inhibitor of the G6P transporter. Hepatic G6P accumulation induces sterol 12α-hydroxylase (Cyp8b1) expression, which is mediated by the major glucose-sensitive transcription factor, carbohy- drate response element-binding protein (ChREBP). Activation of the G6P-ChREBP-CYP8B1 axis increases the rel- ative abundance of cholic-acid–derived bile acids and induces physiologically relevant shifts in bilecomposition. The G6P-ChREBP–dependent change in bile acid hydrophobicity associates with elevated plasma campesterol/cholesterol ratio and reduced fecal neutral sterol loss, compatible with enhanced intestinal cholesterol absorption. Conclusion: We report that G6P, the primary intracellular metabolite of glucose, controls hepatic bile acid synthesis. Our work identifies hepatic G6P-ChREBP-CYP8B1 signaling as a regulatory axis in control of bile acid and cholesterol metabolism. (Hepatology 2019;0:1-14).
Previous studies have shown that detectable levels of BAs are present in testis even in normal physiological condition 5,13 . It is thus interesting to question whether 1/these BAs come from plasma only or could be synthe-
tized by the testis; 2/how BA homeostasis is regulated in different organs like liver and testis and 3/the potential involvement of FXRα in these regulations. In that line, the present study shows that testis could also synthetize BAs. Moreover, the mice invalidated for the gene encoding FXRα have alterations of bile acid homeostasis in liver and testis. The exposure to BAs alters differently the hepatic and the testicular expression of genes involved in BA synthesis in wild type (Wt) and Fxrα−/− males. We show that in the context of FXRα deficiency, BA exposure results in a strong alteration of testis physiology and sperm production via CAR signaling pathways. Indeed, the testicular altered BA pool composition and the production of intermediate metabolites of BA led to the modula- tion of constitutive-androstane-receptor (CAR; NR1I3) signaling pathways within the testis. The involvement of CAR is supported by our data showing that within the testis, exposure to a specific CAR agonist or inverse agonist respectively counteracted or reproduced the phenotype observed in Fxrα−/− mice fed BA-diet.
Animals 2020, 10, 359 8 of 12
A significant increase in serum TC, LDL-C, and TG were observed in the HS pigs after 3 d of heat exposure. The results are in agreement with our previous study, in which TC, LDL-C, and TG were increased on the first three days of heat exposure and gradually returned to the baseline afterward [ 24 ]. An elevated temperature changes the lipid composition and architecture of cell membranes, leading to an increase in membrane fluidify, which could be offset by increasing cholesterol levels [ 28 ]. Indeed, cholesterol levels in the membrane rise with an increase in body temperature to stabilize membranes [ 29 , 30 ]. Cress and Gerner also reported that cholesterol could regulate the survival and sensitivity of mammalian cells to high temperature via changes in physical membrane properties [ 31 ], serving as a primary defense mechanism for upregulation of expression of heat shock proteins (HSPs) [ 14 ] that promotes the survival of stressed cells [ 32 ], leading to resistance to heat stress [ 33 ]. The elevation in serum cholesterol in our study might have served as a primary defense mechanism against the cellular damage and noxious effects during the early stage of heat exposure.
protein-, carbohydrate- and lipid-composition allowed in the formulas, there were only minor differences in caloric intake between groups.
The rhBSSL-effect on growth in SGA infants indicates that the appropriate target popula- tion lies within a subpopulation. While it is often claimed that SGA infants require greater energy supply than AGA infants [ 19 ], there is no consensus on how to feed SGA infants, what the appropriate feeding volumes are, and what the rate of feeding advancement should be [ 20 ]. In this respect our study is consistent with Makrides et al. [ 21 ], showing that high DHA
Adult exposure to CA-diet is known to reduce sperm count and decrease fertility rates. Beside the quantitative impact of BAs on reproductive function, the present study demonstrate that pathological concentrations of BAs are responsible for germ cell epigenetic abnormalities and disease programming on two generations of offspring. The last few years have seen increasing interest in investigating the epigenetic dimension of male fertility defects. Recently, human studies along with experimental model in rodents, describe a strong association between repro- ductive disorders and sperm epimutations. A good illustration come from recent work showing that sperm col- lected for the purpose of Assisted Reproductive Technologies (ART) present abnormal chromatin composition as well as altered DNA methylation patterns 22 . In mouse, exposure to endocrine disruptors such as vinclozoline, a fungicide known for its repro-toxic properties, increases spermatogenic cell apoptosis rate and alters sperm DNA methylation 23 . Interestingly, ART or paternal exposures to vinclozolin have both been associated with offspring phenotypes across multiple generations 22 . In this context, the impacts of supra-physiological BA concentrations on sperm epigenome define an original model of paternal inheritance where metabolic compounds can affect offspring.
Determinants of postprandial plasma bile acid kinetics in human volunteers. Am J Physiol Gastrointest Liver Physiol 313: G300 – G312, 2017. First published June 29, 2017; doi:10.1152/ ajpgi.00157.2017.—Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n ⫽ 72, 62 ⫾ 8 yr, mean ⫾ SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography- tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postpran- dial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmeno- pausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion- transporting polypeptide-1A2 (OATP1A2), was associated with de- layed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota.
Fig 1. CA-supplementation reverse HFD induced overweight. (A) Weight gain of C57BL/6J mice along the experiments. After 90 days of high fat diet (HFD) (red arrow), half of the mice on the HFD (triangles) were switched to HFD supplemented with CA (HF-CA) (squares) (n = 12 –35 per group). Black arrows indicated the timing of fertility test. (B) Relative body weight 4 months after the switch to HF-CA diet. (C) Relative liver weight normalized to body weight in C57Bl/6 mice fed HFD and HF-CA diet 4 months after the switch to HF-CA diet. (n = 18 –25 per group). (D) Plasma bile acid levels and pool composition in mice under HFD or HF-CA diet 4 months after the switch to HF-CA diet. (D) Plasma cholesterol, cholesterol ester, triglycerides and glucose levels in mice fed to HFD or HF-CA diets 4 months after the switch to HF-CA diet. (n = 19 –25 per group). Data represent mean ± SEM; Statistical analyses: * p <0,05; ** p<0,01 and *** p<0,001.
Bile acids, phospholipids, and cholesterol are the major lipid components in human bile. Bile acids account for ~72% of the total lipid pool whereas phospholipids and cholesterol contribute ~24% and ~4% respectively . The composition of bile is altered in various chronic cholestatic diseases [2-8]. The ratio of taurine to glycine conjugated bile acids is especially altered and it has been reported that the taurine conjugates are elevated in cholestatic conditions . Analysis of bile for the quantification of biliary lipids and for the determination of the conjugation pattern of bile acids (with glycine and/or taurine) would be of value in understanding the pathophysiology of cholestatic diseases. The biliary lipid components are generally quantified by conventional techniques such as enzymatic methods, gas chromatography (GC), high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS)/liquid chromatography-mass spectrometry (LC-MS) techniques [10-13]. These methods are tedious, involve multiple steps, and result in longer experimental times . Due to
deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), hyodeoxycholic acid (HDCA) and cholic acid (CA) were purchased from Sigma-Aldrich and dissolved in DMSO to make 500 mM stock solutions. Dihydrotestosterone (DHT; Steraloids Inc., Newport, RI) was dissolved in DMSO to make 100 mM stock solutions. The final concentration of DMSO in culture medium was not greater than 0.2%. The selective caspase substrates Ac-DEVD-AFC, Ac-IETD-AFC and Ac-LEHD-AFC were purchased from Enzo Life Sciences (Farmingdale, NY) and dissolved in DMSO to make 20 mM stock solutions. Caspase inhibitors z-DEVD-fmk and z-IETD-fmk (BD Biosciences, Franklin Lakes, NJ) were dissolved in 100% DMSO to produce 10 mM stock solutions. All primary antibodies were purchased from Cell Signaling (Beverly, MA). LNCaP and PC-3 cells were exposed to 1000-fold dilutions of the appropriate stock solutions of bile acids, DHT and/or caspase inhibitors in their respective experimental culture media. Control cells were exposed to 0.1% or 0.2% DMSO for single or co-exposure experiments, respectively.
Ce chapitre a présenté l’ensemble de la démarche mise en œuvre pour réaliser la composition d’applications. Ce processus s’appuie sur quatre étapes que sont la description des applications existantes à composer, la description de la composition fonctionnelle, la réalisation de la composi- tion d’IHM et pour finir la concrétisation du résultat. La méta-modélisation des applications et de leur composition fonctionnelle met en relief le découpage Noyau Fonctionnel–IHM et les liens qui relient le noyau fonctionnel à l’IHM comme préconisé dans les architectures de type MVC, PAC ou Arch. La représentation choisie est une représentation à base de composants : un composant fonctionnel, un ensemble de composants d’IHM et des liens de données et d’événements entre le composant fonctionnel et les composants d’IHM. Chaque IHM est associée à une ou plusieurs opérations (action) présentes au sein du composant fonctionnel. Les composants d’IHM ne sont associés qu’à un seul composant fonctionnel. Le choix a également été fait de distinguer à la fois des ports de données et des ports d’événement/action afin de dissocier le flot de contrôle et le flot de données que l’on retrouve dans les orchestrations de services par exemple (cf. 3.1.1 ). La repré- sentation qui a été faite de la composition fonctionnelle correspond à un composant composite qui agrège l’ensemble des composants fonctionnels impliqués dans la composition. De la même manière on distingue des ports de données et d’action et on retrouve les deux types de liens que sont les liens de données et d’action.
Composition audio : Alain Thibault Composition visuelle : Yan Breuleux
Extraits de la diffusion pièce à la 5em salle de la Place des arts dans le cadre de la 5e édition du festival Montréal/Nouvelles Musiques (MNM) du 23 au 26 février 2011. Durée : 35 minutes.
6. La composition du projet
Notre objectif est d’identifier la composition du projet processus, une composition qui serait commune à tous les types de projets, des projets d’innovation à ceux opérationnels et quels que soient les objets pour lesquels ils sont établis en tant qu’action organisée. Nous entendons par composition l’ensemble des parties en relation les unes avec les autres qui constituent un projet processus, celui-ci étant conçu comme une totalité organisée. C’est un système d’action fondé sur le couplage entre des actions et des acteurs mais également l’usage de ressources de tous types. Nous tenons pour acquis les enseignements de la théorie systémique des organisations et notamment les modèles proposés par cette théorie et celle de la décision 27 . Un projet processus, comme tous les dispositifs de production, tous les systèmes actifs, des plus élémentaires au plus complexes, est organisé selon les relations entre trois types d’activités majeures qui peuvent être portées de façon spécifique et pérenne par une partie de l’organisation, organisée alors pour ce faire, ou bien portées par une partie qui n’est pas stabilisée pour ce faire mais organisée ou auto organisée localement et momentanément afin de répondre à une sollicitation particulière. Ces trois grandes activités présentes au sein de toute organisation qui décide de ses activités et de son organisation constituent la base canonique, opération, information/coordination et décision (OID). Toute action renvoie à une décision qui l’oriente, au déroulement et à la coordination de multiples activités, en relation généralement circulaire avec la décision. L’identification explicite de cette base canonique OID (opération, information, décision), relève de la systémique. La prenant comme acquis pour le projet processus, la composition recherchée est spécifique à ce type de processus et vise à identifier les grandes catégories d’actions et les grandes catégories d’acteurs qui doivent être organisées pour produire in fine un projet résultat, certes en interrelation avec les activités basiques de décision, de coordination et d’opération.
Abbreviations: BSDL, bile salt-dependent lipase; PDAC, pancreatic adenocarcinoma
Received: October 19, 2015 Accepted: August 13, 2016 Published: September 01, 2016
Pancreatic adenocarcinoma (PDAC) is a dismal disease. The lack of specific symptoms still leads to a delay in diagnosis followed by death within months for most patients. Exon 11 of the bile salt-dependent lipase (BSDL) gene encoding variable number of tandem repeated (VNTR) sequences has been involved in pancreatic pathologies. We hypothesized that BSDL VNTR sequences may be mutated in PDAC. The amplification of BSDL VNTR from RNA extracted from pancreatic SOJ-6 cells allowed us to identify a BSDL amplicon in which a cytosine residue is inserted in a VNTR sequence. This insertion gives rise to a premature stop codon, resulting in a truncated protein and to a modification of the C-terminal amino-acid sequence; that is PRAAHG instead of PAVIRF. We produced antibodies directed against these sequences and examined pancreatic tissues from patients with PDAC and PanIN. Albeit all tissues were positive to anti-PAVIRF antibodies, 72.2% of patient tissues gave positive reaction with anti-PRAAHG antibodies, particularly in dysplastic areas of the tumor. Neoplastic cells with ductal differentiation were not reactive to anti-PRAAHG antibodies. Some 70% of PanIN tissues were also reactive to anti-PRAAHG antibodies, suggesting that the C insertion occurs early during pancreatic carcinogenesis. Data suggest that anti-PRAAHG antibodies were uniquely reactive with a short isoform of BSDL specifically expressed in pre-neoplastic lesions of the pancreas. The detection of truncated BSDL reactive to antibodies against the PRAAHG C-terminal sequence in pancreatic juice or in pancreatic biopsies may be a new tool in the early diagnosis of PDAC.
Dès F. et Stein, et même, sous forme de traces, dans des pièces antérieures (on pense à Insaisies, 1982, et à ses costumes sagement satinés laissant échapper de vertes feuilles de salade), Bagouet reconstruit un corps hétérogène, travaillé par la présence de l’autre à l’intérieur de soi. C’est cette indécelable impureté, cette composition première, qui forme le style inimitable de Bagouet : les lignes pures de Déserts d’amour, dans les corps comme dans l’espace, sont toujours troublées par quelque défaillance. Telle arabesque serait parfaite si le regard n’en était de quelques degrés dévié ; telle diagonale se déploierait superbement si un danseur “dissident” ne s’en échappait. Cette impureté travaille en premier lieu à l’intérieur du corps ; elle dénonce toute hégémonie, ou toute uniformité de la matière. Jusqu’à Assaï, la composition travaille à réunifier le territoire du danseur. Mais dès la pièce suivante, le corps dansant réassuré, c’est toute la danse qui se laisse gagner par l’impureté. Dans Le Saut de l’ange (1987), chef d’œuvre collaboratif de Bagouet et Boltanski, elle détruit toute unité stylistique, gâte les subtils ciselages de l’écriture bagouétienne par de “grosses danses” (les séquences dites des “Zoulous”, notamment), bruyantes et tapageuses, voire grossiè- res. Styles de danse mêlés, costumes hétéroclites sortis d’une (très savante) malle de grenier, espace dis- persé, perspective dissolue, le corps s’y libère des armatures spatiales et structurelles qui l’avaient jusque là étayé.
Corresponding authors: Paul.Van Liedekerke@inria.fr, Dirk.Drasdo@inria.fr
In biological and medical literature, alternative hypotheses for initial bile duct lumen formation during embryogenesis exist, which so far remained largely untested. Guided by the quantification of morphological features and expression of genes in developing bile ducts from embryonic mouse liver, these hypotheses were sharpened and data collected that permitted to develop a high resolution individual-based computational model to test the alternative hypotheses in silico. Simulations with this model suggest that successful bile duct lumen formation primarily requires the simultaneous contribution of directed cell division of cholangiocytes, local osmotic effects generated by salt excretion in the lumen, and temporally-controlled differentiation of hepatoblasts to cholangiocytes, with apical constriction of cholangiocytes only moderately affecting luminal size.
Small heterodimer partner (SHP) is an important transcriptional factor involved in the regulation of glucose, lipid, and bile acid metabolism in liver. Shp has been reported to be down regulated in ovariectomized (Ovx) mice and up-regulated by estrogens suggesting a link between estrogens and Shp. The purpose of the present study was to determine the effects of exercise training on Shp and key markers of cholesterol and bile acid homeostasis in Ovx rats under cholesterol feeding. Our main experimental group was composed of Ovx rats fed a high cholesterol diet (Ovx-Chol) that was compared to a group of Ovx rats fed a standard diet (Ovx-SD) and a group of Sham operated rats fed the cholesterol diet (Sham-Chol). These groups of Ovx and Sham rats were subdivided into either voluntary wheel running or sedentary groups for 5 weeks. Plasma and liver total cholesterol levels were not affected by exercise training in any of the experimental conditions. Cholesterol feeding in both Sham and Ovx rats resulted in significantly (P<0.001) higher hepatic cholesterol accumulation than in Ovx-SD. Hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), which are involved in cholesterol uptake from circulation, were not influenced by training. A main effect of training (P< 0.05) was, however, found for transcripts of Shp and cholesterol 7 alpha-hydroxylase (Cyp7a1), the main gene involved in bile acid biosynthesis from cholesterol. These results suggest that voluntary wheel running may modulate cholesterol metabolism in Ovx animals through up-regulation of Shp and bile acid formation.