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INTRODUCTION: le traitement des larges fistules kysto-biliaires ne fait pas l´unanimitA© des auteurs en l´absence de consensus ou de niveau de preuve A©levA©. Les mA©thodes chirurgicales sont controversA©es entre traitement radical permettant de suturer la fistule en zone saine et le traitement conservateur qui pose des problA¨mes de rA©paration. Le but de cette A©tude est de comparer les diffA©rentes techniques chirurgicales du traitement conservateur des larges fistules kysto-biliaires. METHODES: A©tude rA©trospective de 54 fistules larges, menA©e au service de chirurgie gA©nA©rale du CHU Habib Bourguiba A Sfax durant 9 ans (2010 - 2018). RESULTATS: il s´agit de 44 patients. L´A©chographie abdominale a permis de suspecter une ouverture dans les voies biliaires dans 18 cas (47,4%) alors que la tomodensitomA©trie (TDM), a suspectA© une ouverture chez 28 patients (68.3%). Le traitement des fistules A©tait rA©alisA© par la technique du DITFO dans 18 cas (33,3%), de PERDROMO dans 11 cas (20,4%) et le drainage bipolaire dans 25 cas. Le taux de morbiditA© chirurgicale spA©cifique A©tait de 31,5% dominA© par une fistule biliaire post opA©ratoire dans 18,5% des cas. La technique de DITFO A©tait associA©e A un sA©jour hospitalier le plus court (p=0,028) et une morbiditA© plus basse (22,2%) sans diffA©rence statistiquement significative. CONCLUSION: la technique de DITFO reprA©sente la technique de choix dans le traitement des fistules kysto-biliaires (FKB), elle a une morbiditA© moins A©levA©e et le sA©jour hospitalier le plus court.

Le pancreas ectopique (ou aberrant ou heterotopie pancreatique) se definit par la presence de tissu pancreatique en situation anormale, sans rapport anatomique avec la glande principale. Son incidence est estimee entre 0,5% et 14% sur les series autopsiques, mais est probablement sous-estimee du fait de son caractere le plus souvent asymptomatique. Les localisations habituelles sont representees par le duodenum (30-35%), l´estomac (30%) et le jejunum (15%). Sa localisation hepatique est exceptionnelle. Nous en rapportons un nouveau cas de decouverte fortuite. Il s´agit d´une patiente âgee de 54 ans, hypertendue, operee deux ans auparavant pour un adenocarcinome du sigmoide classe pT3N1b (A). L´evolution etait marquee par l´installation de multiples nodules d´allure secondaire predominant au niveau du lobe hepatique droit (B), d´ou l´instauration d´une chimiotherapie neo-adjuvante (4 cures FOLFOX-ERBITUX). La patiente a beneficie d´une lobectomie droite. L´examen histologique des differents prelevements effectues a confirme la presence d´une localisation secondaire hepatique d´un adenocarcinome moyennement differencie d´origine colorectale avec des limites d´exereses saines. Le foie alentour etait le siege d´une steatose macrovacuolaire non systematisee estimee a 20%. Il s´y associait un foyer d´heterotopie pancreatique englobant des acini et des canaux excreteurs organises en lobule (C, D). Les suites operatoires immediates etaient simples, cependant, l´evolution a ete marquee par la recidive tumorale au niveau du foie gauche.

The aquatic metabolic unit used in this study was cofounded by The Netherlands Organization for Scientific Research (code 805-34.025). Currently it is part of a large-scale EU research facility program. The study was funded by the EU-FP7 project AQUAEXCEL (262336). LM is currently supported by a Fundação para a Ciência e a Tecnologia (FCT) research position (IF/01314/2014/CP1231/CT0001) from Portugal. This study had also the support of FCT through strategic projects UID/Multi/04423/2019 and UID/MAR/04292/2013 granted to CIIMAR and MARE, respectively. SN has support from FCT grant (SFRH/BPD/94500/2013). This work was also supported by the Integrated Programme of SR&TD “Smart Valorization of Endogenous Marine Biological Resources Under a Changing Climate” (reference Centro01-0145-FEDER-000018), co-funded by Centro 2020 program, Portugal 2020, European Union, through the European Regional Development Fund. In aquaculture, fish may be exposed to sub-optimal rearing conditions, which generate a stress response if full adaptation is not displayed. However, our current knowledge of several coexisting factors that may give rise to a stress response is limited, in particular when both chronic and acute stressors are involved. This study investigated changes in metabolic parameters, oxidative stress and innate immune markers in a rainbow trout (Oncorhynchus mykiss) isogenic line exposed to a combination of dietary (electrolyteimbalanced diet, DEB 700 mEq Kg−1 ) and environmental (hypoxia, 4.5 mg O2 L −1 ) challenges and their respective controls (electrolyte-balanced diet, DEB 200 mEq Kg−1 and normoxia, 7.9 or mg O2 L −1 ) for 49 days. At the end of this period, fish were sampled or subjected to an acute stressor (2 min of handling/confinement) and then sampled. Feeding trout an electrolyte-imbalanced diet produced a reduction in blood pH, as well as increases in cortisol levels, hepato-somatic index (HSI) and total energy content in the liver. The ratio between the lactate dehydrogenase (LDH) and isocitrate dehydrogenase (IDH) activities decreased in the liver of trout fed the DEB 700 diet, but increased in the heart, suggesting a different modulation of metabolic capacity by the dietary challenge. Several markers of oxidative stress in the liver of trout, mainly related to the glutathione antioxidant system, were altered when fed the electrolyteimbalanced diet. The dietary challenge was also associated with a decrease in the alternative complement pathway activity (ACH50) in plasma, suggesting an impaired innate immune status in that group. Trout subjected to the acute stressor displayed reduced blood pH values, higher plasma cortisol levels as well as increased levels of metabolic markers associated with oxidative stress in the liver. An interaction between diet and acute stressor was detected for oxidative stress markers in the liver of trout, showing that the chronic electrolyte-imbalance impairs the response of rainbow trout to handling/confinement. However, trout reared under chronic hypoxia only displayed changes in parameters related to energy use in both liver and heart. Taken together, these results suggest that trout displays an adaptative response to chronic hypoxia. Conversely, the dietary challenge profoundly affected fish homeostasis, resulting in an impaired physiological response leading to stress, which then placed constraints on a subsequent acute challenge. info:eu-repo/semantics/publishedVersion

Carnivorous rainbow trout exhibit prolonged postprandial hyperglycemia when fed a diet exceeding 20% carbohydrate content. This poor capacity to utilize carbohydrates has led to rainbow trout being classified as “glucose-intolerant” (GI). The metabolic phenotype has spurred research to identify the underlying cellular and molecular mechanisms of glucose intolerance, largely because carbohydrate-rich diets provide economic and ecological advantages over traditionally used fish meal, considered unsustainable for rainbow trout aquaculture operations. Evidence points to a contribution of hepatic intermediary carbohydrate and lipid metabolism, as well as upstream insulin signaling. Recently, microRNAs (miRNAs), small noncoding RNAs acting as negative posttranscriptional regulators affecting target mRNA stability and translation, have emerged as critical regulators of hepatic control of glucose-homeostasis in mammals, revealing that dysregulated hepatic miRNAs might play a role in organismal hyperglycemia in metabolic disease. To determine whether hepatic regulatory miRNA networks may contribute to GI in rainbow trout, we induced prolonged postprandial hyperglycemia in rainbow trout by using a carbohydrate-rich diet and profiled genome-wide hepatic miRNAs in hyperglycemic rainbow trout compared with fasted trout and trout fed a diet devoid of carbohydrates. Using small RNA next-generation sequencing and real-time RT-PCR validation, we identified differentially regulated hepatic miRNAs between these groups and used an in silico approach to predict bona fide mRNA targets and enriched pathways. Diet-induced hyperglycemia resulted in differential regulation of hepatic miRNAs compared with fasted fish. Some of the identified miRNAs, such as miRNA-27b-3p and miRNA-200a-3p, are known to be responsive to hyperglycemia in the liver of hyperglycemic glucose-tolerant fish and mammals, suggesting an evolutionary conserved regulation. Using Gene Ontology term-based enrichment analysis, we identify intermediate carbohydrate and lipid metabolism and insulin signaling as potential targets of posttranscriptional regulation by hyperglycemia-regulated miRNAs and provide correlative expression analysis of specific predicted miRNA-target pairs. This study identifies hepatic miRNAs in rainbow trout that exhibit differential postprandial expression in response to diets with different carbohydrate content and predicts posttranscriptionally regulated target mRNAs enriched for pathways involved in glucoregulation. Together, these results provide a framework for testable hypotheses of functional involvement of specific hepatic miRNAs in GI in rainbow trout.

International audience; The nutritional transition that the western population has undergone is increasingly associated with chronic metabolic diseases. In this work, we evaluated a diet rich in saturated fatty acids (hyperlipidic, HL) after weaning of the offspring rats submitted to maternal protein restriction on the hepatic mitochondrial bioenergetics. Wistar rats were mated and during gestation and lactation, mothers received control diets (NP, normal protein content 17%) or low protein (LP, 8% protein). After weaning, rats received either NL (normolipidic) or HL (+59% SFA) diets up to 90 days of life. It was verified that all respiratory states of hepatic mitochondria showed a reduction in the LP group submitted to the post-weaning HL diet. This group also presented greater mitochondrial swelling compared to controls, potentiated after Ca(2+) addition and prevented in the presence of EGTA (calcium chelator) and cyclosporin A (mitochondrial permeability transition pore inhibitor). There was also an increase in liver protein oxidation and lipid peroxidation and reduction in catalase and glutathione peroxidase activities in the LP group fed HL diet after weaning. Our data suggest that adult rats subjected to maternal protein restriction were more susceptible to hepatic mitochondrial damage caused by a diet rich in saturated fatty acids post-weaning.

Obesity induced by overfeeding ultimately can lead to nonalcoholic fatty liver disease, whereas dietary fiber consumption is known to have a beneficial effect. We aimed to determine if a supplementation of a mix of fibers (inulin, resistant starch and pectin) could limit or alleviate overfeeding-induced metabolic perturbations. Twenty female minipigs were fed with a control diet (C) or an enriched fat/sucrose diet supplemented (O + F) or not (O) with fibers. Between 0 and 56 days of overfeeding, insulin (+88%), HOMA (+102%), cholesterol (+45%) and lactate (+63%) were increased, without any beneficial effect of fibers supplementation. However, fibers supplementation limited body weight gain (vs. O, −15% at D56) and the accumulation of hepatic lipids droplets induced by overfeeding. This could be explained by a decreased lipids transport potential (−50% FABP1 mRNA, O + F vs. O) inducing a down-regulation of regulatory elements of lipids metabolism / lipogenesis (−36% SREBP1c mRNA, O + F vs. O) but not to an increased oxidation (O + F not different from O and C for proteins and mRNA measured). Glucose metabolism was also differentially regulated by fibers supplementation, with an increased net hepatic release of glucose in the fasted state (diet × time effect, P

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.

A 13-week feeding trial was carried out with juvenile rainbow trout to test two diets: a control diet without astaxanthin (AX) supplementation (CTRL diet), and a diet supplemented with 100 mg/kg of synthetic AX (ASTA diet). During the last week of the feeding trial, fish were exposed to episodic hyperoxia challenge for 8 consecutive hours per day. Episodic hyperoxia induced physiological stress responses characterized by a significant increase in plasma cortisol and hepatic glycogen and a decrease in plasma glucose levels. The decrease of plasma glucose and the increase of hepatic glycogen content due to episodic hyperoxia were emphasized with the ASTA diet. Hyperoxia led to an increase in thiobarbituric acid-reactive substances in the muscle, diminished by dietary AX supplementation in both liver and muscle. Muscle and liver AX were increased and decreased respectively after 7-day episodic hyperoxia, leading to an increase in flesh redness. This augment of muscle AX could not be attributed to AX mobilization, since plasma AX was not affected by hyperoxia. Moreover, hyperoxia decreased most of antioxidant enzyme activities in liver, whereas dietary AX supplementation specifically increased glutathione reductase activity. A higher mRNA level of hepatic glutathione reductase, thioredoxin reductase, and glutamate-cysteine ligase in trout fed the ASTA diet suggests the role of AX in glutathione and thioredoxin recycling and in de novo glutathione synthesis. Indeed, dietary AX supplementation improved the ratio between reduced and oxidized glutathione (GSH/GSSG) in liver. In addition, the ASTA diet up-regulated glucokinase and glucose-6-phosphate dehydrogenase mRNA level in the liver, signaling that dietary AX supplementation may also stimulate the oxidative phase of the pentose phosphate pathway that produces NADPH, which provides reducing power that counteracts oxidative stress. The present results provide a broader understanding of the mechanisms by which dietary AX is involved in the reduction of oxidative status.

La rupture intrapéritonéale du kyste hydatique du foie avec une membrane proligère intacte est rare. Nous rapportons le cas d'une patiente âgée de 63 ans qui avait consulté pour douleur de l'hypochondre droit sans fièvre ni ictère. L'imagerie trouvait un kyste hydatique du segment IV du foie associé à une lésion kystique pelvienne de 12cm x 06cm. L'exploration chirurgicale trouvait un kyste hydatique univésiculaire du foie rompu avec une membrane proligère intacte et libre dans la cavité péritonéale. Le but de ce travail est de rapporter un nouveau cas de rupture intrapéritonéale d'un kyste hydatique du foie avec membrane proligère intacte et de préciser les difficultés diagnostiques et thérapeutiques rencontrées au décours de cette complication.

Objective Hepatic steatosis is the first step leading to non-alcoholic fatty liver disease, which represents a major complication of obesity. Here, we show that MCT1 haploinsufficient mice resist to hepatic steatosis development when fed a high fat diet. They exhibit a reduced hepatic capacity to metabolize monocarboxylates such as lactate compared to wildtype mice. Methods To understand how this resistance to steatosis develops, we used HFD fed wildtype mice with hepatic steatosis and MCT1 haploinsufficient mice to study hepatic metabolism. Results AMPK is constitutively activated in the liver of MCT1 haploinsufficient mice, leading to an inactivation of SREBP1. Therefore, expression of key transcription factors for lipid metabolism, such as PPARα and γ, CHREB, or SREBP1 itself, as well as several enzymes including FAS and CPT1, was not upregulated in these mice when fed a high fat diet. It is proposed that reduced hepatic lactate metabolism is responsible for the protection against hepatic steatosis in MCT1 haploinsufficient mice via a constitutive activation of AMPK and repression of several major elements involved in hepatic lipid metabolism. Conclusion Our results support a role of increased lactate uptake in hepatocytes during HFD that, in turn, induce a metabolic shift stimulating SREBP1 activity and lipid accumulation., Highlights • Lactate uptake causes a shift in LDH isoform expression during HFD. • LDH isoform shift favors a decrease in AMPK activity. • Lactate uptake reduction in MCT1+/− mice blocks LDH isoform shift and leads to AMPK activation. • SREBP activation is prevented in MCT1+/− mice due to AMPK activation. • Decreased expression of SREBP targets involved in lipid metabolism protects against NAFLD.

L'hématome hépatique est une affection méconnue, peut être gravissime et son diagnostic se fait souvent lors de l'autopsie périnatale. Devant une symptomatologie clinique, souvent, non spécifique et un tableau biologique retardé, le diagnostic est basé essentiellement sur l'échographie et le traitement est souvent conservateur. Nous rapportons un cas d'hématome hépatique chez un nouveau-né à terme, asymptomatique dans un contexte de traumatisme obstétrical.Mots clés: Hématome, foie, nouveau-né, traumatisme obstétricalEnglish Title: Hepatic hematoma in neonates: about a caseEnglish AbstractHepatic hematoma is a condition of unrecognized origin which can become extremely serious and whose diagnosis is often made during perinatal autopsy. It is often characterised by nonspecific clinical manifestations and a long delay before biological presentation.The diagnosis is essentially based on ultrasound and treatment is often conservative.We here report a case of a full-term newborn with asymptomatic hepatic haematoma due to obstetrical trauma.Keywords: Hematoma, liver, new-born, obstetrical trauma

International audience; Obesity and its related disorders have been associated with the presence in the blood of gut bacteria-derived lipopolysaccharides (LPS). However, the factors underlying this low-grade elevation in plasma LPS, so-called metabolic endotoxemia, are not fully elucidated. We aimed to investigate the effects of Western diet (WD) feeding on intestinal and hepatic LPS handling mechanisms in a rat model of diet-induced obesity (DIO). Rats were fed either a standard chow diet (C) or a Western Diet (WD, 45% fat) for 6 wk. They were either fed ad libitum or pair-fed to match the caloric intake of C rats for the first week, then fed ad libitum for the remaining 5 wk. Six-week WD feeding led to a mild obese phenotype with increased adiposity and elevated serum LPS-binding protein (LBP) levels relative to C rats, irrespective of initial energy intake. Serum LPS was not different between dietary groups but exhibited strong variability. Disrupted ileal mucus secretion and decreased ileal Reg3-γ and -β gene expression along with high ileal permeability to LPS were observed in WD compared with C-fed rats. Ileal and cecal intestinal alkaline phosphatase (IAP) activity as well as Verrucomicrobia and Bifidobacterium cecal levels were increased in WD-fed rats compared with C-fed rats. WD consumption did not impact mRNA levels of LPS-handling hepatic enzymes. Correlation analysis revealed that ileal passage of LPS, IAP activity, Proteobacteria levels and hepatic aoah gene expression correlated with serum LPS and LBP, suggesting that ileal mucosal defense impairment induced by WD feeding contribute to metabolic endotoxemia.

La rupture spontanée de carcinome hépatocellulaire (CHC) représente une complication relativement rare et potentiellement fatale. Les situations cliniques sont différentes depuis l'hémorragie compensée jusqu'à la rupture péritonéale massive entraînant un hémopéritoine abondant mettant en jeu le pronostic vital. Le diagnostic repose sur le scanner qui détecte la tumeur et l'éventuelle extravasation si le saignement est actif. La mise en évidence de l'extravasation se fait parfois au temps artériel, mais elle est presque toujours visible au temps portal. L'embolisation est le premier traitement en urgence à envisager dans la rupture de CHC ce qui ne préjuge pas d'une autre prise en charge ultérieure en cas d'évolution favorable. Avec un taux de succès dépassant 90%, il s'agit d'une méthode peu invasive en comparaison avec la chirurgie. On peut effectuer soit une embolisation simple, soit d'emblée une chimio-embolisation lipiodolée. Nous rapportons l'observation d'un patient âgé de 60 ans chez qui a été découvert il y a un mois un CHC de 7 cm du foie gauche sur foie cirrhotique. Il avait présenté cinq heures avant sa consultation une épigastralgie brutale et intense associée à une distension abdominale, un retentissement hémodynamique et une déglobulisation (Hb:7,5 g/dl). Le scanner abdominal (A, B) a montré un CHC du foie gauche compliqué d'hémorragie intrapéritonéale de moyenne abondance avec une extravasation du produit de contraste en flaque péritumorale. Après transfusion sanguine et stabilisation de son état hémodynamique, il lui a été réalisé une chimio-embolisation (C, D) permettant de contrôler le saignement. Les suites immédiates étaient favorables.Pan African Medical Journal 2015; 22

Supplementary Data : http://gut.bmj.com/content/early/2016/01/31/gutjnl-2015-310798/suppl/DC1; International audience; OBJECTIVE:Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).DESIGN:We constructed a novel hepatocyte-specific PPARα knockout (Pparα(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.RESULTS:Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparα(hep-/-) mice when compared with Pparα(-/-) mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα(-/-) mice became overweight during ageing while Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) fed a standard diet developed hepatic steatosis in ageing.CONCLUSIONS:Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.

Background Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects. Results Female mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; −13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized. Conclusions This study highlights the high sensitivity of the epigenetic machinery gene expression, and particularly the histone acetylation pathway, to maternal obesity. These obesity-induced transcriptional changes could alter the placental and the hepatic epigenome, leading to FGR. Preconceptional weight loss appears beneficial to fetal growth, but some effects of previous obesity were retained in offspring phenotype. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0188-3) contains supplementary material, which is available to authorized users.

La tuberculose hepatique nodulaire est rare. Nous rapportons une forme pseudo-tumorale dont le tableau clinico-biologique et radiologique initial etait aspecifique. Il s'agit d'un jeune marocain suivi pour maladie de Wilson et presentant une fievre au long cours. L'imagerie met en evidence une lesion nodulaire hepatique non specifique. L'examen anatomo-pathologique au cours d'une biopsie echo guidee du nodule hepatique permit de porter le diagnostic. L'evolution clinique est favorable sous traitement specifique. Key words : Maladie de Wilson, tuberculose, foie

Acknowledgements: George Corsar and Jim MacDonald for the management of experimental animals. We thank Ms Evelyn Argo, Mr Ian Davidson (Proteomics Facility), Ms Gillian Milne (Histology & Electron Microscopy Facility) and Mrs Margaret Fraser (Institute of Medical Sciences) at the University of Aberdeen and NHS Grampian for expert technical assistance and Elodie Poumerol (UMR1198 INRA, transcriptome analysis), Christine Kerr and Mark Osprey (James Hutton Institute, chemical analysis) for technical support.; International audience; The development of fetal ovarian follicles is a critical determinant of adult female reproductive competence. Prolonged exposure to environmental chemicals (ECs) can perturb this process with detrimental consequences for offspring. Here we report on the exposure of pregnant ewes to an environmental mixture of ECs derived from pastures fertilized with sewage sludge (biosolids): a common global agricultural practice. Exposure of pregnant ewes to ECs over 80 day periods during early, mid or late gestation reduced the proportion of healthy early stage fetal follicles comprising the ovarian reserve. Mid and late gestation EC exposures had the most marked effects, disturbing maternal and fetal liver chemical profiles, masculinising fetal anogenital distance and greatly increasing the number of altered fetal ovarian genes and proteins. In conclusion, differential temporal sensitivity of the fetus and its ovaries to EC mixtures has implications for adult ovarian function following adverse exposures during pregnancy.

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia Grant No. 173009; This study aimed to investigate effects of citrus flavanones naringenin (NAR) and hesperetin (HES) on liver antioxidant status and membrane phospholipid composition in 24-month-old rats. NAR and HES (15 mg/kg) were administrated orally to male Wistar rats, once per day, for 4 weeks. Control group received either vehicle (sunflower oil) or remained intact. The results showed decreased (p < 0.05) activity of antioxidant enzymes (AOE), specifically catalase (CAT), superoxide dismutase (SOD) 1 and glutathione reductase (GR) in the liver of intact control old-aged rats in comparison to young intact controls. Flavanone administration to old-aged males increased (p < 0.05) examined AOE activities in comparison to vehicle-administered animals. Namely, NAR was more potent in comparison to HES regarding the increase (p < 0.05) in activities of examined antioxidant enzymes (SOD 1 and 2, glutathione peroxidase-GPx and GR) and the liver glutathione (GSH), while HES elevated (p < 0.05) only activity of CAT and GR. Both flavanones significantly decreased (p < 0.05) TBARS and improved (p < 0.05) membrane phospholipid composition in favor of n-3 PUFA and n-6/n-3 PUFA ratio. Both flavanones did not affect liver histology and reduced (p < 0.05) alanine aminotransferase and aspartate aminotransferase levels in serum. The results of this study indicate beneficial potential of citrus flavanones in the old-aged rat liver

This work was supported by the French National Institute for Health and Medical Research (INSERM), and by the Joseph-Fourier UniversityWe are grateful to Emily Tubbs for language corrections in this paper; The aim of this study was to characterize the early alterations of the liver mitochondrial function in ZDF (fa/fa) rats that develop diabetes compared to that of their lean counterparts ZDF (fa/+). Liver mitochondrial function was examined in 11‐ and 14‐week‐old ZDF (fa/fa) and ZDF lean (fa/+) rats. Oxygen consumption, H2O2 release, calcium retention capacity (CRC), membrane potential, membrane fluidity, and fatty acid composition were analyzed. State 3 oxygen consumption with palmitoyl‐carnitine increases between 11 and 14 weeks of age in lean but not in diabetic animals. This response was not seen with other substrates, suggesting that the use of fatty acids is impaired in diabetic rats. H2O2 release was lower in 14‐week‐old ZDF (fa/fa) rats as compared to ZDF lean (fa/+). These changes were not associated with differences in enzymatic activities of the respiratory complexes, suggesting regulatory mechanisms independent of their expression levels. Membrane fluidity and composition analyses show only slight effects linked to diabetes progression. The most salient feature was a reduction in CRC in the presence of CsA, an effect reflecting PTP dysregulation. Our data suggest few changes of mitochondrial function in ZDF fa/fa rats. At the age of 11 weeks, liver mitochondria have mainly a reduced effect of CsA on CRC.

In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPARα, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPARα axis in which GR directly regulates the transcriptional activation of PPARα by binding to its promoter. Certain PPARα target genes such as Fgf21 remain repressed in the fetal liver and become PPARα responsive after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPARα in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands. DOI: http://dx.doi.org/10.7554/eLife.11853.001, eLife digest Birth is a highly stressful and critical event. In the womb, babies rely on the supply of oxygen and nutrients provided by the placenta. However, once they are born they need to breathe for themselves and gain all their nutrients from suckling milk. The placenta provides a sugar-rich diet, while milk is richer in fat. Failing to cope with this change in diet leads to serious complications and sometimes death. Therefore, a better understanding of how the body adapts to these changes may shed light on pathways that are important for good health in later life. The liver plays a central role in processing the nutrients absorbed by the gut. It uses fats to produce molecules called ketone bodies, such as β-hydroxybutyrate, which are then used as fuel by other tissues and organs including the heart, muscle and the brain. A protein called PPARα controls the production of ketone bodies primarily by regulating genes that are involved in the uptake and breakdown of fat in the liver. However, little is known about how this protein affects the development of the liver. Here, Rando, Tan et al. report that mice start to produce more PPARα in the liver shortly before birth. This ultimately activates several genes that encode enzymes that break down fats. The experiments show that during labor, stress hormones called glucocorticoids directly stimulate the production of PPARα in the liver of the fetus to prepare newborn mice for harnessing energy from fat-rich milk. In the absence of PPARα, mouse liver cells are less able to break down fats after birth and so start to accumulate fat, resulting in fewer ketone bodies being produced. Rando, Tan et al. show that β-hydroxybutyrate regulates some PPARα target genes, including one called Fgf21. The activity of this gene increases only after milk suckling starts and it encodes a protein that enhances the breakdown of fats in the liver. Without PPARα, the expression levels of its target genes, including Fgf21, do not increase after birth, which promotes the build up of fats in liver cells, a condition known as liver steatosis. Overall, the results reported by Rando, Tan et al. highlight how stress during labor plays an important role in priming the body to cope with a fat-rich diet after birth. Future studies will need to determine if stress hormones and ketone bodies could be used as therapies for babies born by caesarean section with liver steatosis. DOI: http://dx.doi.org/10.7554/eLife.11853.002

Nous rapportons le cas exceptionnel d'une patiente de 54 ans prise en charge pour une angiocholite due a un thrombus tumoral, d'une tumeur neuroendocrine primitive (TNE Ive ) du foie , dans la voie biliaire principale. Key words: Angiocholite, tumeur neuroendocrine, foie

Eight young female camels shared in four groups of two 2 years received a basal diet enriched respectively with 0, 2, 4, and 8 mg selenium under sodium selenite form for 64 days. Feed intake was assessed daily; blood samples were taken on weekly basis. One camel from each group was killed at the end of the experiment. Se concentration in serum was increased significantly in the supplemented groups with an average of 176.3 +/- 18.0 ng/mL in the control group, 382.7 +/- 107.6 in the group receiving 2 mg Se, 519.8 +/- 168.4 in the group receiving 4 mg Se, and 533.4 +/- 158.6 in the group receiving 8 mg Se daily. For glutathione peroxidase (GSH-Px) activity, the control group (51.0 IU/g Hb) and the group receiving 2 mg (50.5 IU/g Hb) were significantly different than groups receiving 4 and 8 mg (respectively, 65.9 and 76.1 IU/g Hb). No significant variation occurred for vitamin E (mean, 0.56 +/- 0.23 ng/mL). Significant correlation between serum Se and GSH-Px was reported. Kidney was the richest organ in selenium followed by lung, spleen, and liver, but the increase in supplemented groups was more marked in liver and kidney. The hair seemed to be the best indicator of selenium intake in camel.

Growth hormone (GH) transgenic salmon possesses markedly increased metabolic rate, appetite, and feed conversion efficiency, as well as an increased ability to compete for food resources. Thus, the ability of GH-transgenic fish to withstand periods of food deprivation as occurs in nature is potentially different than that of nontransgenic fish. However, the physiological and genetic effects of transgenic GH production over long periods of food deprivation remain largely unknown. Here, GH-transgenic coho salmon (Oncorhynchus kisutch) and nontransgenic, wild-type coho salmon were subjected to a 3- month food deprivation trial, during which time performance characteristics related to growth were measured along with proximate compositions. To examine potential genetic effects of GH-transgenesis on long-term food deprivation, a group of genes related to muscle development and liver metabolism was selected for quantitative PCR analysis. Results showed that GH-transgenic fish lose weight at an increased rate compared to wild-type even though proximate compositions remained relatively similar between the groups. A total of nine genes related to muscle physiology (cathepsin, cee, insulin-like growth factor, myostatin, murf-1, myosin, myogenin, proteasome delta, tumor necrosis factor) and five genes related to liver metabolism (carnitine palmitoyltransferase, fatty acid synthase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, glucokinase) were shown to be differentially regulated between GH-transgenic and wild-type coho salmon over time. These genetic and physiological responses assist in identifying differences between GH-transgenic and wild-type salmon in relation to fitness effects arising from elevated growth hormone during periods of long-term food shortage

Les cystadenomes hepatiques sont des tumeurs kystiques rares et de diagnostic pre-operatoire difficile en imagerie. Ils touchent le plus souvent des femmes de plus de 50 ans. Une attitude chirurgicale radicale, compte tenu du potentiel malin de ces lesions, est recommandee. Nous rapportons le cas d'une patiente âgee de 22 ans qui a ete operee il y a 4 mois dans un hopital regional a tort pour kyste hydatique du foie, mais en peroperatoire vu l'aspect, il n'a pas ete realise de geste. La biologie hepatique etait normale. La tomodensitometrie abdominale avait objective une masse kystique multiloculaire de 25X13 cm avec des cloisons epaisses de 3 a 5 mm de diametre evoquant un kyste hydatique de type III ou un cystadenome biliaire. L'IRM abdominale a objective une masse kystique cloisonnee bien limitee du foie droit mesurant 23X23X21 cm en hypersignal homogene T2, hyposignal T1 avec des cloisons non rehaussees apres injection de Gadolinium, aspect en faveur d'un cystadenome hepatique. La serologie hydatique etait negative. Il a ete realise dans un premier temps une ligature portale droite a fin d'entrainer une hypertrophie compensatrice du foie gauche en vue d'une resection hepatique droite. Lors de la deuxieme operation, il a ete realise une kystectomie subtotale, avec coagulation de la partie residuelle, en raison des adherences entre le kyste et les structures vasculaires cavo-sushepatiques. L'examen anatomopathologique avait confirme le diagnostic de cystadenome hepatique. Les suites operatoires etaient simples et avec un recul de deux ans, il n'a pas ete note de recidive.

Le kyste hydatique du foie (KHF) est un parasite de developpement lent qui genere des lesions anatomopathologiques variees, responsables de tableaux cliniques divers et polymorphes. Le but du traitement est d'eliminer le parasite, et de regler le probleme de la cavite residuelle et des eventuelles complications associees. Nous rapportons le cas d'un KHF de taille et de topographie inhabituelles puisqu'il prend naissance a partir du foie gauche et plonge le long du petit epiploon pour passer en retro-gastrique et pre-pancreatique et refoulant tres bas le colon transverse. Patiente agee de 34 ans, aux antecedents familiaux d'hydatidose, presentant depuis deux mois une douleur de l'hypocondre droit a type de pesanteur. Il existait une masse palpable occupant l'hypocondre droit, l'epigastre et le flanc gauche. Le scanner abdominal a montre une volumineuse formation kystique multiloculaire faisant 20*15*10 cm etendue du foie gauche jusqu'au flanc gauche evoquant un volumineux KHF. La serologie hydatique etait positive. La patiente a ete operee par une sous-costale droite elargie a gauche. Le KHF etait volumineux et occupait la totalite du foie gauche qui est atrophie. Le kyste etait ouvert en retro et sous gastrique pour evacuer son contenu qui est multi-vesiculaire et bilieux. Il a ete realise une resection du dome saillant, une fermeture de deux fistulettes kysto-biliaires (objectivees par la cholangiographie per-operatoire et l'epreuve au bleu de methylene), une epiplooplastie et un drainage de la cavite residuelle. Les suites operatoires immediates et lointaines etaient simples en particulier pas de recidive hydatique avec un recul d’un an.

Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol·kg−1·min−1) peripherally, the PePo group received GLP-1 (1 pmol·kg−1·min−1) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol·kg−1·min−1) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group ( n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 (∼50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 ± 1.3 and 10.6 ± 1.0 vs. 5.7 ± 1.0 and 5.4 ± 0.8 μmol·kg−1·min−1, respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.

Les angiomes hépatiques sont des tumeurs bénignes du foie les plus fréquentes. Ils touchent tous les âges mais souvent des adultes avec une prédominance féminine. Souvent la lésion est unique de taille inférieure à 1 cm dans la moitié des cas. Elle peut être double ou multiple dans certains cas.Nous rapportons l'observation d'un patient de 40 ans sans antécédent notable qui présente depuis une semaine des douleurs isolées de l'hypochondre droit. L'examen clinique trouve un patient en bon état général avec une légère sensibilité de l'hypochondre droit. L'échographie abdominale est revenue en faveur d'un foie augmenté de taille de contours réguliers et d'échostructure hétérogène, siège d'une lésion nodulaire au niveau du segment VI et VII de 86 mm de grand axe. Le scanner abdominal montre un foie augmenté de taille de contours réguliers et de densité homogène, siège d'une volumineuse masse hypodense à centre liquidien, occupant tout le foie droit, mesurant 17 x 9 cm avec un rehaussement discontinu périphérique en motte au temps artériel (A) et un remplissage progressif et centripète aux temps portal et tardif (B).

International audience; Fast-growing chickens have a limited ability to tolerate high temperatures. Thermal manipulation during embryogenesis (TM) has previously been shown to lower chicken body temperature (Tb) at hatching and to improve thermotolerance until market age, possibly resulting from changes in metabolic regulation. The aim of this study was to evaluate the long-term effects of TM (12 h/d, 39.5°C, 65% RH from d 7 to 16 of embryogenesis vs. 37.8°C, 56% RH continuously) and of a subsequent heat challenge (32°C for 5 h at 34 d) on the mRNA expression of metabolic genes and cell signaling in the Pectoralis major muscle and the liver. Gene expression was analyzed by RT-qPCR in 8 chickens per treatment, characterized by low Tb in the TM groups and high Tb in the control groups. Data were analyzed using the general linear model of SAS considering TM and heat challenge within TM as main effects. TM had significant long-term effects on thyroid hormone metabolism by decreasing the muscle mRNA expression of deiodinase DIO3. Under standard rearing conditions, the expression of several genes involved in the regulation of energy metabolism, such as transcription factor PGC-1α, was affected by TM in the muscle, whereas for other genes regulating mitochondrial function and muscle growth, TM seemed to mitigate the decrease induced by the heat challenge. TM increased DIO2 mRNA expression in the liver (only at 21°C) and reduced the citrate synthase activity involved in the Krebs cycle. The phosphorylation level of p38 Mitogen-activated-protein kinase regulating the cell stress response was higher in the muscle of TM groups compared to controls. In conclusion, markers of energy utilization and growth were either changed by TM in the Pectoralis major muscle and the liver by thermal manipulation during incubation as a possible long-term adaptation limiting energy metabolism, or mitigated during heat challenge.

Scope High-fat (HF) diets contribute to the development of cardiovascular diseases and the metabolic syndrome. This study was undertaken to investigate the beneficial effects of Vineatrol®-enriched red wines on blood lipids, oxidative stress and inflammation, and the role of some metabolic pathway regulatory proteins. Methods and results Golden Syrian hamsters received an HF diet for 13 wk, in the presence or absence of red wines supplemented with Vineatrol® (RWV) or not. The HF diet increased plasma cholesterol, triglycerides, glucose, and insulin, which were attenuated by RWV treatment. RWV protected against the HF-induced increase in liver nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and spared antioxidant enzyme activities. RWV did not reduce either liver steatosis or increased plasma leptin due to the HF diet, but greatly improved adiponectinemia. In the liver, RWV affected the inflammatory response by decreasing polymorphonuclear cell number and lowering TNF-α and IL-6 levels. Moreover, the increase in NF-κB activity in the HF group liver was prevented by RWV. Finally, RWV partially corrected low SIRT1 levels due to the HF diet but had no influence on SIRT3 or p-AMPK protein levels. Conclusion Our studies suggest that RWV is capable of reversing the atherogenic process induced by an HF diet in hamster tissues.

We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages (r2 = 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain.—Bretillon, L., D. Lütjohann, L. Ståhle, T. Widhe, L. Bindl, G. Eggertsen, U. Diczfalusy, and I. Björkhem. Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J. Lipid Res. 2000. 41: 840–845.

International audience; Two Rhode Island Red egg-laying lines have been divergently selected on residual food intake (low intake R$^-$ line, high intake R$^+$ line) for 19 generations. In addition to direct response, correlated responses have altered several other traits such as carcass adiposity and lipid contents of several tissues, the R$^+$ animals being leaner than the R$^-$ ones. In a search for the biological origin of the differences observed in fat deposit, the hepatic mRNA amounts of genes involved in lipid metabolism were investigated. No difference was found between lines for mRNA levels of ATP citrate-lyase, acetyl-CoA carboxylase, fatty acid synthase, malic enzyme and CCAAT/enhancer binding protein $\alpha$, a transcription factor acting on several lipogenesis genes. The genes coding for stearoyl-CoA desaturase and apolipoprotein A1 displayed significantly lower mRNA levels in the R$^+$ cockerels compared to the R$^-$. All together these mRNA levels explained 40% of the overall variability of abdominal adipose tissue weight, suggesting an important role of both genes in the fatness variability.; Expression hépatique de gènes de la lipogénèse chez des lignées divergentes de poules pondeuses sélectionnées sur la consommation alimentaire résiduelle. Deux lignées de poules pondeuses Rhode Island Red ont été sélectionnées de façon divergente sur la consommation alimentaire résiduelle (R$^-$/R$^+$) pendant 19 générations. En plus de la réponse directe à la sélection, des réponses corrélées ont été observées sur d'autres caractères comme l'adiposité de la carcasse et le taux de lipides de plusieurs tissus, les animaux de la lignée R$^+$ étant plus maigres que ceux de la lignée R$^-$. Afin d'identifier l'origine biologique des différences observées dans l'état d'engraissement, les niveaux d'ARNm de gènes impliqués dans le métabolisme des lipides ont été étudiés. Aucune différence d'accumulation n'a été trouvée entre lignées concernant les ARNm de l'ATP citrate-lyase, l'acétyl-CoA carboxylase, la synthase des acides gras, l'enzyme malique et le facteur de transcription CCAAT/enhancer binding protein $\alpha$ qui agit sur plusieurs gènes de la lipogénèse. Les niveaux d'ARNm des gènes codant la stéaroyl-CoA désaturase et l'apolipoprotéine A1 sont significativement plus faibles chez les animaux de la lignée R$^+$ que chez ceux de la lignée R$^-$. Ces deux taux d'ARNm expliquent ensemble 40 % de la variabilité du poids de tissu adipeux abdominal entre les deux lignées, suggérant un rôle important de ces deux gènes dans la variabilité de l'état d'engraissement.

Mme A.M âgée de 29 ans multipare avec antécédent de cholécystotomie, a consulté pour douleur pelvienne chronique sans autre signes gynécologiques, digestifs ou urinaires chez qui l'examen trouve une masse abdomino- pelvienne arrivant jusqu'à l'ombilic rénitente sensible. Au toucher vaginal complété par le toucher rectale, la taille de l'utérus est difficile à apprécier avec perception du pole inférieur de la masse. l'échographie pelvienne objective une image kystique dépassant l'écran, à contenu finement échogène, comportant une cloison incomplète épaisse (17mm) non vascularisée, l'utérus sans anomalie et les ovaires non pas été visualisés, par ailleurs pas d'épanchement intra-peritoneal , l'IRM pelvienne n'a pas été réalisée par manque de moyens. Ainsi une laparotomie exploratrice a été réalisée en ayant évoqué l'origine ovarienne maligne en premier lieu, cependant l'exploration a trouvé un kyste énorme appendu au ligament rond du foie, tandis que l'appareil génital interne était macroscopiquement intègre. Une résection du kyste au niveau de son collet - en collaboration avec les viscéralistes-a été réalisée après aspiration de son contenu qui été légèrement hématique. L'examen macroscopique de la pièce a trouvé de multiples fines cloisons incomplètes sur la paroi interne du kyste. Les suites opératoires étaient simples. L'examen anatomopathologique est revenu en faveur d'un kyste bénin du ligament rond du foie.

Background and Aims: High protein (HP) diets are suggested to positively modulate obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease in humans and rodents. The aim of our study was to detect mechanisms by which a HP diet affects hepatic lipid accumulation. [br/] Methods: To investigate the acute and long term effect of high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35 energy%) or low (10 energy%) fat and high (50 energy%) or normal (15 energy%) protein diets for 1 or 12 weeks. Effects on body composition, liver fat, VLDL production rate and the hepatic transcriptome were investigated. [br/] Results: Mice fed the HP diets displayed a lower body weight, developed less adiposity and decreased hepatic lipid accumulation, which could be attributed to a combination of several processes. Next to an increased hepatic VLDL production rate, increased energy utilisation due to enhanced protein catabolic processes, such as transamination, TCA cycle and oxidative phosphorylation was found upon high protein ingestion. [br/] Conclusion: Feeding a HP diet prevented the development of NAFLD by enhancing lipid secretion into VLDL particles and a less efficient use of ingested calories.

Chickens mimic an insulin-resistance state by exhibiting several peculiarities with regard to plasma glucose level and its control by insulin. To gain insight into the role of insulin in the control of chicken transcriptome, liver and leg muscle transcriptomes were compared in fed controls and “diabetic” chickens, at 5 h after insulin immuno-neutralization, using 20.7K-chicken oligo-microarrays. At a level of false discovery rate

Le kyste hydatique du foie est une parasitose qui sévit à l´état endémique au maroc. La rupture dans la paroi abdominale et dans le psoas est une complication exceptionnelle. Nous rapportons un cas de kyste hydatique du foie rompu dans la paroi et dans le muscle psoas. Le diagnostic a été établi sur les données de l´échographie et surtout de la tomodensitométrie. Le patient a été opéré avec des suites simples.Key words: Kyste hydatique, rupture, abdomen, foie, psoas, Maroc

We describe here an in vitro technique to assess the estrogenic activity of chemicals. This technique is based on rainbow trout hepatocytes incubated in a basic medium free of any additional growth factors or estrogenic chemicals and uses the production of vitellogenin (VTG) as a marker for the estrogenic potency of the compounds tested. The system allows at least some of the metabolic transformations which are undertaken by the liver cells in vivo and could therefore be used for xenobiotic compounds which exhibit estrogenic activities after liver metabolic transformation. A dose-response curve was always consistently obtained using estradiol-17β (E 2 ), with a mid point at around 100 nM E 2 and a maximum response at around 1000 nM. Established estrogens such as 17 a 1 ethynylestradiol (EE 2 ) or diethylstilboestrol (DES) were also tested. EE 2 appeared to be equipotent with E 2 and DES slightly less potent. E 2 conjugates were, perhaps surprisingly, also very potent. Estradiol-3-sulfate was equipotent with E 2 and estradiol-17β-glucuronide approx. 10% as potent. Other steroids such as androgens and progesterone, though active in the bioassay, were 3 orders of magnitude less potent than E 2 . Of the various steroids tested, only cortisol, at concentrations up to 50 μM, was completely inactive. Six different phytoestrogens were tested in the assay. All were weakly estrogenic, possessing approximately one thousanth the potency of E 2 (they were as potent as the endrogens and progesterone). All six phytoestrogens, as well as the androgens and progesterone, were tested in the presence of tamoxifen. In all cases tamoxifen reduced the production of VTG significantly, demonstrating that the estrogenic action of all of these compounds was most likely mediated by the E 2 receptor. The potencies determined here may not reflect the situation in vivo but can provide complementary results about the activity of chemicals which need an hepatic metabolization to be estrogenic. Hepatocyte cultures would profitably be developed in other species to sustain these results.

International audience; Glucose homeostasis exhibits several peculiarities in chickens (in short, presence of high glycemia and resistance to high doses of exogenous insulin). Though the full chicken glucokinase gene sequence is still lacking, several results suggest its existence. The functionality of chicken glucokinase (GK) has been further investigated using an activator of mammalian GK (GKA). In vitro, GKA decreased GK's S0.5(a) in a glucose-dependent manner in liver homogenates from either fasted or fed chickens; it also increased GK Vmax(a) in homogenates from fed chickens. In vivo, acute oral GKA administration (10-100 mg/kg) induced a potent and dose dependent hypoglycemic effect in fed chickens (starting between 15 and 45 min with a maximum effect at 40 mg/kg, P < 0.0001). At this dose, plasma insulin levels showed erratic and minor changes in the early times (an increase at 5 min and a decrease at 10 min, P < 0.05). At 90 min, when hypoglycemia had developed plasma insulin levels decreased under controls and plasma pancreatic glucagon levels increased over controls. Also at 40 mg/kg, GKA transiently inhibited food intake at about 3 h (P < 0.0001). In conclusion, GKA is a potent activator of chicken GK evidencing that the structure and the activity of chicken GK are similar to those of mammalian GK. At variance with results obtained in mammals, the potent GKA hypoglycemic action appears to rely mostly on an effect on liver GK in chicken. This fits with previous results and further support the hypothesis of a "deficient coupling" between B-cell metabolism and insulin release in this species. (C) 2010 Elsevier Inc. All rights reserved.

Contradictory studies suggest IGF-I in fish liver and gills is involved in osmoregulation, but nothing is known about the kidney and intestine's role nor about IGF-II's role in any organ. Tilapia were transferred from freshwater (FW) to seawater (SW) for 1 week (wk) and retransferred to FW for another week. At 4 h, 1 d, 2 d, 3 d and 1wk after SW-transfer and FW-retransfer IGF-I, IGF-II and growth hormone receptor (GHR1) mRNA were measured by real-time PCR. Hepatic IGF-I, IGF-II and GHR1 mRNA were downregulated in parallel after SW-transfer, recovered and were again downregulated after FWretransfer. In gills, IGF-I, IGF-II andGHR1were upregulated synchronously after SW-transfer and, partially also after FW-retransfer. The renal genes were downregulated after SW-transfer and partially upregulated after FW-retransfer. Persisting upregulation in intestinal IGF-I mRNA occurred after FW-retransfer. Thus, endocrine and auto/paracrine IGF-I and IGF-II seem to be involved in fish osmoregulation in an organ-specific manner. =

International audience; Skiba-Cassy S, Lansard M, Panserat S, Medale F. Rainbow trout genetically selected for greater muscle fat content display increased activation of liver TOR signaling and lipogenic gene expression. Am J Physiol Regul Integr Comp Physiol 297: R1421-R1429, 2009. First published August 26, 2009; doi: 10.1152/ajpregu.00312.2009.-Genetic selection is commonly used in farm animals to manage body fat content. In rainbow trout, divergent selection for low or high muscle fat content leads to differences in utilization of dietary energy sources between the fat muscle line (FL) and the lean muscle line (LL). To establish whether genetic selection on muscle fat content affects the hepatic insulin/nutrient signaling pathway, we analyzed this pathway and the expression of several metabolism-related target genes in the livers of the two divergent lines under fasting and then refeeding conditions. Whereas glycemia returned to basal level 24 h after refeeding in FL trout, it remained elevated in the LL trout. Target of rapamycin (TOR) protein was more abundant in the livers of FL trout than in LL trout, and refeeding activation of the hepatic TOR signaling pathway (TOR, S6K1, and S6) was therefore enhanced. Genes related to glycolysis (glucokinase and pyruvate kinase) and gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) were only slightly affected by refeeding and genetic selection. Refeeding stimulated expression of lipogenic genes and the sterol-responsive element binding protein (SREBP1), and expression of fatty acid synthase, glucose-6-phosphate dehydrogenase, and serine dehydratase was predominant in the livers of FL fish compared with LL fish. In agreement with recent findings linking TOR to lipogenesis control, we concluded that genetic selection for muscle fat content resulted in overactivation of the TOR signaling pathway-associated lipogenesis and probably also improved utilization of glucose.

International audience; Panserat S, Skiba-Cassy S, Seiliez I, Lansard M, Plagnes-Juan E, Vachot C, Aguirre P, Larroquet L, Chavernac G, Medale F, Corraze G, Kaushik S, Moon TW. Metformin improves postprandial glucose homeostasis in rainbow trout fed dietary carbohydrates: a link with the induction of hepatic lipogenic capacities? Am J Physiol Regul Integr Comp Physiol 297: R707-R715, 2009. First published June 24, 2009; doi: 10.1152/ajpregu.00120.2009.-Carnivorous fish are poor users of dietary carbohydrates and are considered to be glucose intolerant. In this context, we have tested, for the first time in rainbow trout, metformin, a common anti-diabetic drug, known to modify muscle and liver metabolism and to control hyperglycemia in mammals. In the present study, juvenile trout were fed with very high levels of carbohydrates (30% of the diet) for this species during 10 days followed by feeding with pellets supplemented with metformin (0.25% of the diet) for three additional days. Dietary metformin led to a significant reduction in postprandial glycemia in trout, demonstrating unambiguously the hypoglycemic effect of this drug. No effect of metformin was detected on mRNA levels for glucose transporter type 4 (GLUT4), or enzymes involved in glycolysis, mitochondrial energy metabolism, or on glycogen level in the white muscle. Expected inhibition of hepatic gluconeogenic (glucose-6-phosphatase, fructose1,6-bisphosphatase, and phosphoenolpyruvate carboxykinase) mRNA levels was not found, showing instead paradoxically higher mRNA levels for these genes after drug treatment. Finally, metformin treatment was associated with higher mRNA levels and activities for lipogenic enzymes (fatty acid synthase and glucose-6-phosphate dehydrogenase). Overall, this study strongly supports that the induction of hepatic lipogenesis by dietary glucose may permit a more efficient control of postprandial glycemia in carnivorous fish fed with high carbohydrate diets.

International audience; Glucose homeostasis is impaired by a paradoxical interaction between metformin and insulin in carnivorous rainbow trout. Am J Physiol Regul Integr Comp Physiol 297: R1769-R1776, 2009. First published September 30, 2009; doi:10.1152/ajpregu.00369.2009.-Utilizing rainbow trout (Oncorhynchus mykiss) as a known model of a "glucose-intolerant" and poor dietary glucose user, we assessed glucose utilization in fish chronically receiving two molecules able to improve glucose homeostasis: insulin and metformin. Our objectives were to assess the ability of rainbow trout to deal with a glucose load and to improve glucose utilization in fish receiving a chronic administration of insulin plus metformin treatments. Fish received (implanted miniosmotic pumps) saline, insulin, metformin, and insulin plus metformin solution for 4 days and then were subjected to a glucose challenge (intraperitoneal injection) to study glucose homeostasis, analyzing plasma glycemia, mRNA levels of glucose metabolism-related proteins, insulin signaling, and glycogen levels in liver and muscle. Control fish received a saline pump implantation and saline intraperitoneal injection. We found no evidence that the "glucose intolerance" in this species could be linked to any of the molecular markers of metabolism in the tissues analyzed. By contrast, very interestingly, we show for the first time, that metformin is not only unable to improve glucose homeostasis in trout, but, in fact, its counteracts the effects of insulin, creating an "insulin resistance," especially in the muscle. These results make trout an attractive original model to study both insulin and metformin effect on biological systems.

Background Liver-to-pancreas conversion offers new possibilities for β-cell engineering for type 1 diabetes therapy. Among conceivable sources of liver cells, we focused on BMEL cells. These untransformed mouse embryonic liver cells have been reproducibly isolated from different inbred mice strains and have the potential to differentiate into hepatocytes and cholangiocytes in vitro and in vivo. Findings Strikingly, we find here that adherent BMEL cells display functional similarities with multipotent pancreatic precursor cells, namely Pdx1 and Ngn3 expression, and further express Hnf6 in floating aggregate culture. Hes1, a direct repressor of Ngn3 and pancreatic endocrine commitment, is expressed in adherent BMEL cells and decreases with time in aggregate culture. However, Hes1 decrease fails to initiate activation of late-stage pancreatic endocrine transcription factors. Conclusion Here we report that BMEL cells present features of pancreatic endocrine progenitor cells. In the field of diabetes research, BMEL cells are of potential interest for the study of inductive signals critical for in vitro β-cell maturation in-liver-to-pancreas conversion.

International audience; We recently provided evidence of the presence of glucokinase (GCK) in the chicken liver [Berradi, H., Taouis, M., Cassy, S., Rideau, N., 2005. Glucokinase in chicken (Gallus gallus). Partial cDNA cloning, immunodetection and activity determination. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 141, 129-1391. In the present study we addressed the question of whether nutritional regulation of GCK occurs. Several nutritional conditions were compared in chickens (5 weeks old) previously trained to meal-feeding. One group was left in the fasted state (F: 24 h) and one was tested at the end of the 2 h meal (refed: RF). Two other 2 h meal-refed groups received an acute oral saccharose load (6 ml/kg BW) just before the 2 h meal and were sacrificed either at the end of the meal (Saccharose refed, SRF) or 3 h later (SRF+3). Liver GCK mRNA and protein levels did not differ between F, RF and SRF chickens but were significantly increased in SRF+3 chickens (2-fold, p < 0.05). GCK activity did not differ between F and RF chickens but increased significantly in SRF and SRF+3 chickens (1.7-fold, p < 0.05). Chicken liver GCK expression (mRNA and protein) and activity were therefore inducible in these chickens by feeding a meal with acute oral administration of carbohydrate. These and recent findings demonstrating insulin dependency of the liver GCK mRNA and protein strongly suggest that GCK may have an important role in carbohydrate metabolism, including that of the chicken. However, even in these highly stimulatory conditions, liver GCK activity remained relatively low in comparison with other species. The latter result may partly explain the high plasma glucose level in the chicken. (C) 2008 Elsevier Inc. All rights reserved.

Rats with carnitine deficiency due to trimethylhydrazinium propionate (mildronate) administered at 80 mg/100 g body weight per day for 10 days developed liver steatosis only upon fasting. This study aimed to determine whether the transient steatosis resulted from triglyceride accumulation due to the amount of fatty acids preserved through impaired fatty acid oxidation and/or from up-regulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by approximately 13-fold and, in fasted rats, lowered the palmitate oxidation rate by 50% in the perfused organ, increased 9-fold the triglyceride content, and doubled the hepatic very low density lipoprotein secretion rate. Concomitantly, triglyceridemia was 13-fold greater than in controls. Hepatic carnitine palmitoyltransferase I activity and palmitate oxidation capacities measured in vitro were increased after treatment. Gene expression of hepatic proteins involved in fatty acid oxidation, triglyceride formation, and lipid uptake were all increased and were associated with increased hepatic free fatty acid content in treated rats. In periepididymal adipose tissue, mildronate markedly increased lipoprotein lipase and hormone-sensitive lipase activities in fed and fasted rats, respectively. On refeeding, carnitine-depleted rats exhibited a rapid decrease in blood triglycerides and free fatty acids, then after approximately 2 h, a marked drop of liver triglycerides and a progressive decrease in liver free fatty acids. Data show that up-regulation of liver activities, peripheral lipolysis, and lipoprotein lipase activity were likely essential factors for excess fat deposit and release alternately occurring in liver and adipose tissue of carnitine-depleted rats during the fed/fasted transition.

Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n = 10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n = 10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min ( P1). In P2, glucose was infused intraportally (3–4 mg·kg−1·min−1), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min ( P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg·kg−1·min−1) in CON and DEN were 55 ± 3 and 54 ± 4 in the peripheral periods and 55 ± 3 and 55 ± 4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg·kg−1·min−1) in CON averaged 1.7 ± 0.3 during PE and increased to 2.9 ± 0.3 during P2. NHGU (mg·kg−1·min−1) was greater in DEN than CON ( P < 0.05) during PE (2.9 ± 0.4) and failed to increase significantly (3.2 ± 0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.

Recent evidence has emerged that peroxisome proliferator-activated receptor α (PPARα), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARα influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARα plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARα on a potential PPARα response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARα gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARα in peripheral clocks.

The present work aimed to study in rats whether substitution of a low level of fish oil (FO; 2.2% of calories) into a low-fat diet (6.6% of calories from fat as peanut-rape oil or control diet) 1) has a tissue-specific effect on insulin signaling pathway and 2) prevents dexamethasone-induced alteration of insulin signaling in liver, muscle, and adipose tissue. Sixteen rats were used for study of insulin signaling, and sixteen rats received an oral glucose load (3 g/kg). Eight rats/group consumed control diet or diet containing FO over 5 wk. Four rats from each group received a daily intraperitoneal injection of saline or dexamethasone (1 mg·kg−1·day−1) for the last 5 days of feeding. In liver, FO decreased phosphatidylinositol 3′-kinase (PI 3′-kinase) activity by 54% compared with control diet. A similar result was obtained in muscle. In both liver and muscle, FO clearly amplified the effect of dexamethasone. FO did not alter early steps of insulin signaling, and in muscle GLUT4 protein content remained unaltered. In adipose tissue, FO increased PI 3′-kinase activity by 74%, whereas dexamethasone decreased it by 65%; inhibition of PI 3′-kinase activity by dexamethasone was similar in rats fed FO or control diet, and GLUT4 protein content was increased by 61% by FO. Glycemic and insulinemic responses to oral glucose were not modified by FO. In conclusion, FO increased PI 3′-kinase activity in adipose tissue while inhibiting it in liver and muscle. The maintenance of whole body glucose homeostasis suggests an important role of adipose tissue for control of glucose homeostasis.

International audience; Sa and the Sa/So ratio are very sensitive biomarkers of exposure to fumonisins in several species. We previously demonstrated that increases in Sa and in the Sa/So ratio in serum were less pronounced when ducks ingested fumonisins for more than 7 weeks than when animals were exposed for only 1–2 weeks [S.T. Tran, D. Tardieu, A. Auvergne, J.D. Bailly, R. Babil´e, S. Durand, G. Benard, P. Guerre, Serum sphinganine and the sphinganine to sphingosine ratio as biomarker of dietary fumonisins during chronic exposure in ducks, Chem. Biol. Interact., in press]. The aim of this study was to investigate the kinetics of Sa and of the Sa/So in both liver and kidney of ducks that have been previously tested for Sa and the Sa/So ratio in serum. Analysis were performed on treatment days 0, 7, 14, 28 and 77 in five groups of ducks fed fumonisins obtained from an extract of Fusarium verticillioides culture material by daily gavage to obtain an exposure equal to 0, 2, 8, 32 and 128 mg FB1/kg feed. Sa and the Sa/So ratio in tissues were then correlated with Sa and the Sa/So ratio previously obtained in serum. The amounts on sphinganine 1-phosphate (Sa1P) and sphingosine1-phosphate (So1P) in the liver were also investigated. On day 7 of treatment, 2 mg/kg FB1 in the feed were sufficient to increase Sa and the Sa/So ratio in liver (by 165 and 148%, respectively) and kidney (by 193 and 104%, respectively). At a rate of 128 mg/kg FB1 in the feed, a very high increase in Sa concentration was observed in both liver and kidney without mortality and/or signs of necrosis (respective increase of 2034 and 3768%). Although the precise mechanism of the resistance of ducks to fumonisin-induced hepatotoxicity is still uncertain, it might be linked to the rate at which the sphingoid bases sphinganine and sphingosine are converted to their 1-phosphate or other metabolite and eliminated from target tissues.

There are two types of congenital vascular disorders affecting the liver in small animals : portosystemic shunts, object of extensive studies and publications, and arteriovenous fistulae (HAVF), which on the contrary are poorly documented in veterinary medicine. In hepatic arteriovenous fistulae (HAVF), part of the hepatic arterial circulation communicates directly with the portal system within the hepatic parenchyma. This disorder affects young animals. Symptoms include ascites, delayed growth and occasionally neurological signs due to multiple portocaval shunts resulting from the portal hypertension. Surgical treatment includes 1) resection of the affected lobe(s), 2) ligation of the hepatic artery branch feeding the fistula, or 3) endovascular embolization of the artery. The prognosis of this condition is fair and though the success rate of surgical treatments is non-negligible. In most cases, post-surgical treatment includes medication and a special diet (low in proteins). The overall survival rate is comparable to that seen in intrahepatic portosystemic shunts., La pathologie vasculaire congénitale du foie chez les carnivores domestiques est divisée en 2 entités : les shunts porto-systémiques, qui ont fait l’objet de nombreuses études et publications et les fistules artério-veineuses (FAVH), à l’inverse peu documentées en médecine vétérinaire. Lors de FAVH, une partie de la vascularisation artérielle hépatique communique avec le système porte au sein du parenchyme hépatique. Cette affection touche les animaux jeunes. Les symptômes rencontrés sont : ascite, retard de croissance et parfois, signes neurologiques, dus aux shunts porto-caves multiples résultant de l’hypertension portale. Il existe 3 modalités de traitement chirurgical : 1) résection du ou des lobe(s) hépatique(s) concerné(s), 2) ligature de la branche de l’artère hépatique desservant la fistule ou 3) embolisation par voie endovasculaire de l’artère au niveau de la communication artério-veineuse. Le pronostic de cette affection est variable, bien que le taux de succès thérapeutique soit non négligeable. Dans la plupart des cas, les animaux traités chirurgicalement doivent recevoir des médicaments après l’opération et suivre un régime alimentaire particulier (pauvre en protéines). Le taux de survie est globalement comparable à celui observé lors de shunts porto-systémiques intrahépatiques., Chanoit Guillaume, Kyles Andrew, Weisse Chick, Hardie Elisabeth. Les fistules artério-veineuses hépatiques chez le chien : diagnostic, traitement, pronostic. In: Bulletin de l'Académie Vétérinaire de France tome 158 n°4, 2005. pp. 393-397.

Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in four groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (−120 to −30 min), basal (−30 to 0 min), and experimental periods (Exp; 0–240 min). During Exp, somatostatin, intraportal insulin [at basal (Ins groups) or 4-fold basal rates (INS groups)], basal intraportal glucagon, and peripheral glucose (to double hepatic glucose load) were infused. In the Fluv-Ins ( n = 7) and Fluv-INS groups ( n = 6), saline was infused intraportally from 0 to 90 min ( P1), and fluvoxamine was infused intraportally at 2 μg·kg−1·min−1from 90 to 240 min ( P2). Sal-Ins ( n = 9) and Sal-INS ( n = 8) received intraportal saline in P1 and P2. NHGU during P2 was 8.4 ± 1.4 and 6.9 ± 2.3 μmol·kg−1·min−1in Sal-Ins and Fluv-Ins, respectively (not significant), and 13.3 ± 2.2 and 20.9 ± 3.1 μmol·kg−1·min−1( P < 0.05) in Sal-INS and Fluv-INS. Unidirectional (tracer-determined) hepatic glucose uptake was twofold greater ( P < 0.05) in Fluv-INS than Sal-INS. Net hepatic carbon retention during P2 was significantly greater in Fluv-INS than Sal-INS (18.5 ± 2.7 vs. 12.2 ± 1.9 μmol·kg−1·min−1). Nonhepatic glucose uptake was reduced in Fluv-INS vs. Sal-INS (20.0 ± 1.3 vs. 38.4 ± 5.4 μmol·kg−1·min−1, P < 0.05). Intraportal fluvoxamine enhanced NHGU and net hepatic carbon retention in the presence of hyperinsulinemia but not euinsulinemia, suggesting that hepatocyte-targeted SSRIs may reduce postprandial hyperglycemia.