Depot-specific differences in perilipin and hormone-sensitive lipase expression in lean and obese

<p>Abstract</p> <p>Background</p> <p>Mainly dependent on hormone-sensitive lipase, lipolysis is differently impaired between fat depots in human obesity. Perilipin A expression is a critical element in adipocyte lipolysis. The present study aimed at comparing expression and subcellular distribution of perilipin and hormone-sensitive lipase in two abdominal adipose tissues of lean and obese women. We examined whether regional differences in perilipin expression contribute to impaired lipolytic rates.</p> <p>Methods</p> <p>Abdominal subcutaneous and omental adipose tissues were obtained from six lean and ten obese women. We measured total protein content and relative distribution of hormone-sensitive lipase and perilipin proteins between lipid and non-lipid fractions in tissue homogenates. Hormone-sensitive lipase and perilipin mRNA levels, adipocyte size, basal (non-stimulated) and noradrenaline-stimulated lipolysis in isolated adipocytes were determined.</p> <p>Results</p> <p>Adipocytes were significantly larger in the obese versus the lean women and in subcutaneous versus omental fat. Expressed as a function of cell number, basal lipolysis and noradrenaline responsiveness were higher in subcutaneous versus omental adipocytes from the obese women (P < 0.05). Despite higher or identical mRNA levels in the lean and the obese subjects and in subcutaneous and omental tissues, perilipin protein expression was lower in both depots in the obese versus the lean women, and in subcutaneous versus omental in both lean and obese women (P < 0.05). Perilipin was mostly (above 80%) present in the lipid fraction in both depots from the obese patients and the value decreased to 60% in the lean subjects (P < 0.05). Perilipin protein expression was inversely correlated to adipocyte size and basal lipolysis in both depots. Despite higher mRNA levels, hormone-sensitive lipase protein expression decreased in both depots of the obese women. Regional difference for hormone-sensitive lipase was reported in lipid fraction of subcutaneous fat of the obese subjects: hormone-sensitive lipase content was twice as low as in omental adipose tissue.</p> <p>Conclusion</p> <p>In both fat depots, a reduced perilipin protein expression was observed in women obesity. Perilipin protein level may contribute to differences in basal lipolysis and in adipocyte size between fat depots and may regulate lipid accumulation in adipocytes. Differences in hormone-sensitive lipase subcellular distribution were reported between fat depots in the obese women.</p

LCA of municipal solid waste incineration in France: from comprehensive site‐ specific data to Life Cycle Inventory modeling

In France, Municipal Solid Waste (MSW), including non-hazardous waste from economic activities collected together with post-consumer waste, are primarily incinerated (approximately 30% in 2010; ADEME, 2012). Yet, current Life Cycle Inventory databases do not precisely account for the characteristics of waste incineration in the specific French context, in particular with respect to air emissions, use of reactants, energy recovery rates and treatment of bottom ashes. This study accordingly aims at collecting environmental and energy data specific to French incinerators for their further integration into a dedicated Life Cycle Inventory model. The results of data collection and analysis are focused at in this presentation. Data were collected considering 90 French incinerators, respectively operated by SITA, TIRU and VEOLIA, and representing approximately 73% of the total mass of MSW incinerated in France as of 2012. Firstly, French incineration installations were classified according to their abatement technologies. Wet systems (with liquid emissions) combined with electrostatic precipitators and semi dry/semi wet systems combined with a fabric filter are predominant in France regarding dedusting and acid gas treatment (they respectively represent 34 and 25% of the total amount of waste incinerated). At the same time, Selective Catalytic Reduction (high temperature) combined with reactants for Dediox (36%) and Selective Non-Catalytic Reduction combined with reactants for Dediox (32%) are predominant with respect to NOx and dioxin abatement. Secondly, data of process-specific emissions (NOx, particles, dioxins, etc.) have been collected, considering 90 incinerators and 3 years in a raw (2012 to 2014), for their further statistical treatment by category of abatement technology. The correlation between emission factors and abatement technologies is discussed. Considering each kind of emission factor, a distribution of values is accordingly associated either with a given technology of abatement or with the whole French incineration installations. In addition, building on the mass balance at the scale of one French incineration plant, transfer coefficients are calculated in order to further infer waste-specific emissions (e.g. metals) in the model for Life Cycle Inventory of waste incineration in France. Finally, additional data relative respectively to energy (recovery and consumption), to the use of reactants and to downstream treatment of bottom ashes were collected and further statistically treated, considering the 90 incinerators under study. In particular, MSW appear to be incinerated primarily (55%) in plants cogenerating heat and electricity. As a conclusion, the potential use of these data in a Life Cycle Inventory model dedicated to French incineration is more specifically discussed. Acknowledgements This study was partly funded by the French Environment and Energy Management Agency (ADEME) in the framework of the PCI project. The authors wish to thank Patrick Boisseau (TIRU), Jacques Giacomoni (VEOLIA), Lionel Kosior (SITA) and Cédrik Priault (VEOLIA) for their contributions to this work. Reference: ADEME, 2012. L’incinération des déchets ménagers et assimilés. Les avis de l’ADEME. Décembre 2012

Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model – the Zucker diabetic rat

<p>Abstract</p> <p>Background</p> <p>Diabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients. It is characterized by excessive lipids accumulation, with increased triacylglycerol (TAG) stores, and fibrosis in left ventricle (LV). The mechanisms responsible are incompletely known and no specific treatment is presently defined. We evaluated the possible usefulness of two molecules promoting lipid oxidation, fenofibrate and metformin, in an experimental model of DCM, the Zucker diabetic rat (ZDF).</p> <p>Methods</p> <p>ZDF and controls (C) rats were studied at 7, 14 and 21 weeks. After an initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until final studies (at 14 or 21 weeks). C rats received no treatment. Each study comprised measurements of metabolic parameters (plasma glucose, TAG, insulin levels) and sampling of heart for histology and measurements of TAG content and relevant mRNA concentration.</p> <p>Results</p> <p>ZDF rats were insulin-resistant at 7 weeks, type 2 diabetic at 14 weeks and diabetic with insulin deficiency at 21 weeks. Their plasma TAG levels were increased. ZDF rats had at 7 weeks an increased LV TAG content with some fibrosis. LV TAG content increased in untreated ZDF rats at 14 and 21 weeks and was always higher than in C. Fibrosis increased also moderately in untreated ZDF rats. Metformin and fenofibrate decreased plasma TAG concentrations. LV TAG content was decreased by metformin (14 and 21 weeks) and by fenofibrate (14 weeks). Fibrosis was reduced by fenofibrate only and was increased by metformin. Among the mRNA measured, fenofibrate increased Acyl-CoA Oxidase mRNA level, metformin decreased Acyl-CoA Synthase and increased AdipoR1 and pro-inflammatory mRNA levels.</p> <p>Conclusion</p> <p>Fenofibrate had favourable actions on DCM. Metformin had beneficial effect on TAG content but not on fibrosis. PPARα agonists could be useful for the prevention and treatment of DCM.</p

Increased Atherosclerosis in Mice Deficient in Perilipin1

<p>Abstract</p> <p>Background</p> <p>Perilipin1, a lipid droplet associated protein has an important role in the regulation of lipolysis and lipid storage in adipocytes. Perilipin1 is also expressed in foam cells of atheroma plaques and could therefore play a role in the accumulation of lipids in arterial wall and in the development of atherosclerosis. The aim of the study was to investigate this possible role of perilipin1 in atherogenesis.</p> <p>Methods</p> <p>Mice deficient in perilipin1 (<it>Plin1-/-) </it>were crossed with <it>Ldlr-/- </it>mice. <it>Ldlr-/- </it>and <it>Plin1-/- Ldlr-/- </it>mice received an atherogenic diet during 10 or 20 weeks. Blood pressure and plasma lipids concentrations were measured. Aortas were collected at the end of the atherogenic diet periods for quantification of atheroma lesions (<it>en face </it>method), histological and immunohistological studies</p> <p>Results</p> <p><it>Ldlr-/- </it>and <it>Plin1-/- Ldlr-/- </it>mice had comparable blood pressure and plasma lipids levels. <it>Plin1-/- Ldlr-/- </it>mice had a lower body weight and decreased adiposity. The atherosclerotic lesion area in <it>Plin1-/-Ldlr-/- </it>mice was moderately increased after 10 weeks of atherogenic diet (ns) and significantly higher after 20 weeks (p < 0.01). Histology of atheroma plaques was comparable with no sign of increased inflammation in <it>Plin1-/- Ldlr-/- </it>mice.</p> <p>Conclusion</p> <p>Perilipin1 ablation in mice results in increased atherosclerosis independently of modifications of risk factors such as raised blood pressure or plasma lipids levels. These data strongly support an atheroprotective role for perilipin1.</p

Thyroid hormone receptor {beta} (TR{beta}) and liver X receptor (LXR) regulate carbohydrate response element binding protein (ChREBP) expression in a tissue selective manner.

Thyroid hormone- (TR) and Liver X- (LXR)receptors are transcription factors involved in lipogenesis. Both receptors recognize the same consensus DNA response element in vitro. It was previously shown that their signalling pathways interact in the control of cholesterol elimination in the liver. In the present study ChREBP, a major transcription factor controlling the activation of glucose-induced lipogenesis in liver, is characterized as a direct target of thyroid hormones(TH) in liver and white adipose tissue(WAT), the two main lipogenic tissues in mice. Using genetic and molecular approaches ChREBP is shown to be specifically regulated by TRbeta, but not by TRalpha in vivo even in WAT where both TR isoforms are expressed. However this isotype specificity is not found in vitro. This TRbeta specific regulation correlates with the loss of TH-induced lipogenesis in TRbeta-/- mice. Fasting/refeeding experiments show that TRbeta is not required for the activation of ChREBP expression particularly marked in WAT following refeeding. However TH can stimulate ChREBP expression in WAT even under fasting conditions suggesting completely independent pathways. Since ChREBP has been described as an LXR target, the interaction of LXR and TRbeta in ChREBP regulation was assayed both in vitro and in vivo. Each receptor recognizes a different response element on the ChREBP promoter, located only eight base pairs apart.There is a crosstalk between LXR and TRbeta signalling on the ChREBP promoter in liver but not in WAT where LXR does not regulate ChREBP expression. The molecular basis for this crosstalk has been determined in in vitro systems

Lipogenesis in arterial wall and vascular smooth muscular cells: regulation and abnormalities in insulin-resistance

<p>Abstract</p> <p>Background</p> <p>Vascular smooth muscular cells (VSMC) express lipogenic genes. Therefore <it>in situ </it>lipogenesis could provide fatty acids for triglycerides synthesis and cholesterol esterification and contribute to lipid accumulation in arterial wall with aging and during atheroma.</p> <p>Methods</p> <p>We investigated expression of lipogenic genes in human and rat arterial walls, its regulation in cultured VSMC and determined if it is modified during insulin-resistance and diabetes, situations with increased risk for atheroma.</p> <p>Results</p> <p>Zucker obese (ZO) and diabetic (ZDF) rats accumulated more triglycerides in their aortas than their respective control rats, and this triglycerides content increased with age in ZDF and control rats. However the expression in aortas of lipogenic genes, or of genes involved in fatty acids uptake, was not higher in ZDF and ZO rats and did not increase with age. Expression of lipogenesis-related genes was not increased in human arterial wall (carotid endarterectomy) of diabetic compared to non-diabetic patients. <it>In vitro</it>, glucose and adipogenic medium (ADM) stimulated moderately the expression and activity of lipogenesis in VSMC from control rats. LXR agonists, but not PXR agonist, stimulated also lipogenesis in VSMC but not in arterial wall <it>in vivo</it>. Lipogenic genes expression was lower in VSMC from ZO rats and not stimulated by glucose or ADM.</p> <p>Conclusion</p> <p>Lipogenic genes are expressed in arterial wall and VSMC; this expression is stimulated (VSMC) by glucose, ADM and LXR agonists. During insulin-resistance and diabetes, this expression is not increased and resists to the actions of glucose and ADM. It is unlikely that this metabolic pathway contribute to lipid accumulation of arterial wall during insulin-resistance and diabetes and thus to the increased risk of atheroma observed in these situations.</p

Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients

Utilisation des lipides : oxydation ou stockage ?

The stability of body weight and composition requires an equilibrium between the intakes and outputs of energy and macronutrients. Fat mass depends on the equilibrium between the input and output of lipid but also on the metabolic fate of lipids (oxidation or storage). Examination of metabolic pathways and of their regulation shows that cells have efficient biochemical and molecular mechanisms to stimulate acutely and on the long term carbohydrate oxidation, lipogenesis and lipid storage and to inhibit lipid oxidation. On the contrary, the ability of cells to acutely stimulate lipid oxidation is limited. These differences in regulation of lipid and carbohydrate metabolism are also present at the whole body level. The ability to increase lipid oxidation in response to an increased lipid intake is still more reduced in obese subjects. Despite numerous attempts to develop pharmacological approaches, modifications of dietary intakes and physical exercise remain the best ways to reduce lipid storage and to increase fat oxidation

Expressions comparées de la lipase hormono-sensible et de la périlipine dans les tissus adipeux sous-cutané et omental des sujets témoins et obèses

Nous avons montré que l'existence d'une lipase hormono-sensible (LHS) tronquée et inactive dans le tissu adipeux de sujets obèses induit une diminution de la lipolyse des adipocytes in vitro. Nous avons ensuite déterminé l'expression et la répartition de la LHS et de la Périlipine entre cytosol et gouttelette lipidique des adipocytes des tissus adipeux sous-cutané et omental de sujets obèses et témoins. La périlipine est surtout présente dans la fraction lipidique tandis que la LHS est également répartie entre les deux fractions, quelque soit le tissu adipeux et les sujets considérés. Il n'y a aucune différence de concentrations de protéine LHS entre les deux tissus, tandis que celles de la Périlipine sont plus importantes dans le tissu viscéral. Le rapport Périlipine/HSL dans la fraction lipidique n'est pas modifié chez les obèses suggérant que la balance entre ces protéines d'action opposée sur la lipolyse n'est pas changéeLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Métabolisme du cholestérol chez l'homme (effet du fénofibrate et expression des gènes régulateurs dans la plaque d'athérome)

La prévention et le traitement de l'athérosclérose nécessitent la réduction des facteurs de risque d'athérome et la compréhension des mécanismes conduisant à l'accumulation de cholestérol dans les cellules spumeuses de la plaque d'athérome. Les fibrates, ligands agonistes des récepteurs nucléaires PPAR , réduisent le risque d'athérome, en particulier par leur action hypolipidémiante. Nous avons montré dans une première étude que cette amélioration du profil lipidique par les fibrates chez des sujets diabétiques de type 2 implique une réduction de la lipogenèse hépatique, participant à la baisse des triglycérides plasmatiques, et une stimulation de l'expression du transporteur ABCA1, protéine clef de l'efflux de cholestérol hors des cellules et de la voie de retour du cholestérol, favorisant l'augmentation des concentrations d'HDL-cholestérol. Dans une deuxième étude nous avons comparé l'expression de gènes régulateurs du métabolisme du cholestérol dans les plaques d'athérome carotidien humain par rapport au tissu artériel situé au voisinage de la plaque. Les quantités de protéine ABCA1 sont diminuées de manière majeure dans la plaque, ce qui réduit les capacités d'efflux de cholestérol, alors que l'expression de CD36, impliqué dans la captation du cholestérol, est augmentée. Ces deux modifications favorisent le dépôt de cholestérol. De plus l'expression de protéines entourant les gouttelettes lipidiques, ADRP et périlipine, est au contraire augmentée dans les plaques. Si lors rôle est comparable à celui décrit dans les adipocytes, ces deux protéines pourraient contribuer aussi à la constitution et au maintien des dépôts de cholestérol dans la plaqueLYON1-BU.Sciences (692662101) / SudocSudocFranceF