Chromatin has a compact organization in which most DNA sequences are structurally inaccessible and functionally inactive. Reconfiguration of thechromatir required to activate transcription. This reconfiguration is achieved by the action of enzymes that covalently modify nucleosomal core histones, and by enzymes that disrupt histone-DNA interactions via ATP hydrolysis. TheSWI/SNF family of ATP-dependent chromatin remodeling enzymes has been implicated not only in gene activation but also in numerous cellular processes including differentiation, gene repression, cell cycle control, recombination and DNA repair. PPARγ, C/EBPα and C/EBPβ are transcription factors with well established roles in adipogenesis. Ectopical expression of each of these factors in non-adipogenic cells is sufficient to convert them to adipocyte-like cells. To determine the requirements of SWI/SNF enzymes in adipocyte differentiation, we introduced PPARγ, C/EBPα or C/EBPβ into fibroblasts that inducibly express dominant-negative versions of the Brahma-Related Gene 1 (BRG1) or human Brahma (BRM), which are the ATPase subunits of the SWI/SNF enzymes. We found that adipogenesis and expression of adipocyte genes were inhibited in the presence of mutant SWI/SNF enzymes. Additionally, in cells expressing C/EBPα or C/EBPβ, PPARγ expression was SWI/SNF dependent. These data indicate the importance of these remodeling enzymes in both early and late gene activation events. Subsequently, we examined by chromatin immunoprecipitation (ChIP) assay the functional role of SWI/SNF enzymes in the activation of PPARγ2, the master regulator of adipogenesis. Temporal analysis of factors binding to the PPARγ2 promoter showed that SWI/SNF enzymes are required to promote preinitiation complex assembly and function. Additionally, our studies concentrated on the role of C/EBP family members in the activation of early and late genes during adipocyte differentiation. During adipogenesis, C/EBPβ and δ are rapidly and transiently expressed and are involved in the expression of PPARγ and C/EBPα, which together activate the majority of the adipocyte genes. Our studies determined the temporal recruitment of the C/EBP family at the promoters of early and late genes by ChIP assay during adipocyte differentiation. We found that all of the C/EBP members evaluated are present at the promoters of early and late genes, and the binding correlated with the kinetics of the C/EBPs expression. Binding of C/EBPβ and δ is transient, subsequently being replaced by C/EBPα. These studies demonstrated that C/EBPβ and δ are not only involved in the regulation of PPARγ and C/EBPα, but also in the activation of late expressed adipocyte genes.

O receptor CD40 e seu ligante CD40L possuem um papel importante na interface entre a resposta imune inata e a adaptativa. Disfunções desta via de sinalização são descritas em doenças de origem inflamatória e autoimunes. Em Lúpus eritematoso sistêmico (LES) foi descrito um aumento nos níveis séricos de CD40L solúvel, que participa na produção de autoanticorpos. Receptores ativados por proliferadores de peroxisomos (PPARs) são fatores de transcrição que inicialmente foram descritos como envolvidos apenas no metabolismo lipídico, mas que atualmente são também descritos como atuantes no controle da resposta imune. Com isso, nosso objetivo é determinar se a ativação dos PPARs modula o processo inflamatório através da interação com CD40/CD40L in vitro ou in vivo. Células de linhagem monocítica humana THP-1 foram tratadas por 24 horas com forbol-éster (PMA, 40 nM) e posteriormente estimuladas com CD40L recombinante (rhCD40L, 1 g/ml) por diferentes períodos. Transcritos de mRNA foram analisados por real time PCR e os resultados expressos como razão da expressão do gene housekeeping GAPDH. As células THP-1 apresentam um aumento na expressão de PPAR e após 16 e 2 horas de estímulo com rhCD40L, respectivamente. Estas células também foram estimuladas com LPS (10 g/ml) e LPS+rhCD40L para sabermos se a resposta obtida anteriormente era específica ao estímulo com rhCD40L. O resultado mostra que há uma diminuição na expressão de PPAR e após o estimulo com LPS ou LPS+rhCD40L, indicando que nessas condições a modulação da expressão de PPARs é especifica para a via de sinalização CD40/CD40L. Foi medida também a expressão de CD36, que é descrito na literatura como um indicador da atividade de PPARs. O resultado mostra que o estímulo com CD40L promove um aumento de CD36, o que indica indiretamente que o PPAR estava ativo neste modelo experimental. Para mostrar a interação direta destas duas vias de sinalização, silenciamos o gene de PPAR por siRNA e posteriormente anlisamos a expressão de CD80, cuja expressão encontra-se aumentada logo após a ativação do CD40 de acordo com a literatura. O resultado mostra que, com o silenciamento de PPAR , há um aumento de CD80 logo após a ativação do CD40, evidenciando assim a interação entre essas duas vias de sinalização. A fim de verificar se os achados encontrados in vitro poderiam ser observados in vivo, foi isolada a fração mononuclear de sangue periférico de pacientes com LES com a doença em atividade (n=17), a doença inativa (n=21) ou doadores saudáveis (n=12) e foi medida a expressão de PPAR e por real time PCR. PPAR apresenta um aumento em pacientes com a doença ativa ou inativa em comparação aos doadores saudáveis. Já a expressão de PPAR apresenta aumento apenas em lúpicos em atividade quando comparados com lúpicos inativos ou doadores saudáveis. Quando considerado nesta análise o efeito do tratamento dos pacientes com corticosteróides nos níveis de PPAR, obsevou-se que a expressão de PPAR apresenta o mesmo padrão anterior. Estes resultados sugerem a hipótese de que PPAR seja um possível marcador de atividade de LES. Para confirmar esta especificidade, foram adicionadas à analise células mononucleares retiradas de pacientes com tuberculose e com infecções agudas. Os dados mostram que os níveis elevados de PPAR se mantém apenas em pacientes com lúpus ativo, o que confirma nossa hipótese. Nossos achados sugerem que PPAR e são regulados especificamente em reposta a ativação da via do CD40/CD40L, em monócitos em cultura e em células obtidas de pacientes com LES. Podemos também sugerir que PPAR possa ser um marcador para a atividade de LES. Estes resultados podem representar um novo mecanismo de controle da via de sinalização do CD40/CD40L, participando no controle da resposta inflamatória em cultura e em células de pacientes lúpicos / The membrane receptor CD40 and its ligand CD40L play an important role in the interface between innate and acquired immunity. Dysfunction of this signaling pathway was described in inflammatory and autoimmune diseases. In systemic lupus erythematosus (SLE), increased serum levels of soluble CD40L have been detected, where it plays a significant role in the generation of auto-antibodies. Peroxisome proliferator activator receptors (PPARs) are transcription factors originally described in lipid metabolism. More recently, they were also characterized as inflammatory modulators. Therefore, our objective was to determine whether the activation of PPARs may modulate the inflammatory process through interaction with the CD40/CD40L signaling pathway in vitro and in vivo. Macrophages derived from the human monocytic cell line THP-1 by 24h-treatment with PMA (40 nM) were stimulated with human recombinant CD40L (rhCD40L, 1 g/ml) for different periods. Messenger RNA (mRNA) transcripts for PPAR , and were determined by real time PCR and expressed as a ratio of the housekeeping gene GAPDH transcripts. THP-1 cells express a basal level of PPAR and gene transcription, which is increased 16 and 2 hours after exposure to rhCD40L, respectively. We also stimulated the THP-1 cells with LPS (10 g/ml) and LPS+rhCD40L to see if the increase of PPAR was a response specific to the rhCD40L stimuli. The data show that there is a decrease in PPAR and genes expression upon LPS or LPS+rhCD40L stimulation, indicating that in these times (2 and 16 hours) the response is specific for the CD40/CD40L signaling pathway. Increased expression of CD36 is known as an indicator of PPARs activity. We measured CD36 and saw an increase of this receptor after rhCD40L stimulus, indicating indirectly that PPARs were active in this experimental model. To prove the direct interaction between CD40/CD40L and PPAR , we silenced the PPAR gene by siRNA and analyzed the expression of CD80, which is known to increase after CD40 activation. The results show an increase in CD40L-stimulated CD80 expression upon silencing of PPAR , showing that there is an interaction between these signaling pathways. To confirm whether these findings also occur in vivo, mononuclear cells were isolated from whole blood samples from SLE patients with active (n=17) and inactive disease (n=21), and healthy donors (n=12). The mRNA transcripts for PPARs were detected by real time PCR. In both active and inactive SLE patients, monocytes show an increase in PPAR mRNA expression, as compared to healthy donors. PPAR mRNA is increased only in active patients when compared to healthy donors and inactive lupus patients. Further in this analysis, when we separated the patients with and without the administration of corticosteroids, PPAR displayed the same pattern as above. These results suggested that PPAR may be a marker for lupus activity. To validate this hypothesis, we compared the results obtained from patients with tuberculosis and acute infections. Results showed that only active-lupus patients have an increase in PPAR , confirming the specificity of this phenomenon and hence our hypothesis Our findings suggest that PPAR and are up-regulated specifically in response to CD40/CD40L activation, in both cultured macrophages and in monocytes obtained from SLE patients. We could also suggest that PPAR may be marker for lupus activity. Our results may represent a new control mechanism of the CD40/CD40L signaling pathway and seem to be implicated in the control of the inflammatory response in both human macrophages in vitro and SLE patients

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:44:52Z No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:46:45Z (GMT) No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-15T12:46:45Z (GMT). No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-20 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / To verify the relationship between the polymorphisms rs18011282 in PPAR-gamma gene and rs429358 + rs7412 in apolipoprotein E gene and lipid profile of adolescents under cardiovascular risk factors. Material and methods: The study sample was composed of 115 adolescents aged 10-19 years, which presented cardiovascular risk factors. The students were evaluated regarding socioeconomic, anthropometric, biochemical, genetic and dietetic variables. ANOVA or Kruskal-Wallis tests were used in the analysis of ungrouped genotypes, while Student’s t-test or Mann-Whitney test were applied to the analysis of the grouped genotypes. Results: The overweight adolescents presented lower HDL-c concentrations (p=0.0016). Those carrying PPAR-gamma Ala allele showed higher serum TAG (p=0.0423) and VLDL-c (p=0.0410) levels when compared to those carrying the Pro allele. For the apolipoprotein E gene polymorphism, it was observed a tendency of higher TAG (p=0.0712) and VLDL-c (p=0.0758) levels in the adolescents carrying the E4 allele when compared to those who did not carry this allele. Conclusion: The polymorphisms PPAR-gama rs18011282 and apolipoprotein E rs429358 + rs7412 seem to be related to the development of lipid profile alterations in adolescents. / Verificar a relação dos polimorfismos rs18011282 no gene do PPAR-gama e rs429358 + rs7412 no gene da apolipoproteína E com o perfil lipídico de adolescentes com fatores de risco cardiovascular. Material e métodos: A amostra foi constituida por 115 adolescentes com idade entre 10-19 anos e com fatores de risco cardiovascular. Os estudantes foram avaliados quanto as variáveis socioeconômicas, antropométricas, bioquímicas, genéticas e dietéticas. Os testes ANOVA ou Kruskal-Wallis foram utilizados para os genótipos não agrupados, e as análises dos genótipos agrupados foram realizadas por meio dos testes t de Student e Mann-Whitney. Resultados: Os adolescentes com excesso de peso apresentaram concentrações inferiores de HDL-c (p=0,0016). Carreadores do alelo variante Ala (PPAR-gama) apresentaram concentrações séricas superiores de TG (p=0,0423) e de VLDL-c (p=0,0410) em relação ao carreadores do alelo selvagem Pro. Para o polimorfismo no gene da ApoE foram observadas concentrações séricas de TG (p=0,0712) e de VLDL-c (p=0,0758) marginalmente maiores nos carreadores do alelo E4 em relação aos não carreadores deste alelo. Conclusão: Os polimorfismos rs18011282 no gene que codifica o PPAR-gama e rs429358 + rs7412 no gene que codifica a ApoE podem estar relacionados ao desenvolvimento de dislipidemias em adolescentes.

Overweight and obesity are associated with Type 2 Diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictorexpress mature adipocyte markers but develop a striking lipid storage defect. In vivo,this results in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARgand ChREBP. These include genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, the gene encoding its substrate and insulin effector. Finally, we reveal a potential novel mTORC2 target, ACSS2, which might control intracellular acetyl-CoA availability and regulate metabolic gene expression by altering histone modification in white adipocytes. Exploring this pathway may uncover strategies to promote safe lipid storage and improve insulin sensitivity.

No description available.

It is well established that continual consumption of a diet high in fat leads to the development of chronic conditions such as obesity, cardio metabolic syndrome, and atherosclerosis that are associated with high incidence of cardiovascular disease. Recent studies have identified endotoxin-derived inflammation as a major diving force for the development of these conditions. Our laboratory has recently demonstrated that consumption of a single high-fat meal results in acute postprandial endotoxemia and alters monocyte cell surface adhesion molecule expression and scavenger receptor CD36 expression. These collective projects describe our efforts to understand the physiological significance of these postprandial changes and if supplementation with spore-based probiotics are able to provide any form of protection against these responses that are associated with the onset of atherogenesis.

No description available.

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Este trabalho teve como objetivo investigar os efeitos da telmisartana (agonista PPAR-gama parcial), losartana (puro bloqueador do receptor AT1 da angiotensina II) e rosiglitazona (agonista PPAR-gama) em modelo experimental de síndrome metabólica. Os alvos do estudo foram a pressão arterial, metabolismo de carboidratos, resistência insulínica, inflamação, tecido adiposo e fígado. Camundongos C57BL/6 (a partir de 3 meses de idade) foram alimentados com dieta padrão (SC, n = 10) ou dieta hiperlipídica rica em sal (HFHS, n = 40) por 12 semanas. Após esse tempo, os animais do grupo HFHS foram subdivididos em 4 grupos (n = 10): HFHS (sem tratamento), ROSI (HFHS tratado com rosiglitazona), TELM (HFHS tratado com telmisartana) e LOS (HFHS tratado com losartana) por 5 semanas. O grupo HFHS apresentou um significante ganho de peso e aumento da pressão arterial sistólica, hiperinsulinemia com resistência insulínica, hiperleptinemia, hipertrofia de adipócitos bem como um quadro de esteatose hepática e níveis aumentados da citocina inflamatória interleucina-6 (IL-6). Os animais tratados com telmisartana chegou ao final do experimento com massa corporal similar ao grupo SC, com reversão do quadro de resistência insulínica, com pressão arterial normal, adipócitos de tamanho normal e sem apresentar esteatose hepática. Além disso, o tratamento com telmisartana aumentou a expressão de PPARγ e adiponectina no tecido adiposo epididimal. A expressão da proteína desacopladora-1 (UCP-1) no tecido adiposo branco (TAB) também foi aumentada. O tratamento com losartana diminuiu a pressão arterial para valores normais, porém com menores efeitos nos parâmetros metabólicos dos animais. O presente modelo experimental de ganho de peso e hipertensão induzidos por dieta mimetiza a síndrome metabólica humana. Neste modelo, a telmisartana aumentou a expressão de UCP-1 no TAB, preveniu o ganho de peso e melhorou a sensibilidade à insulina e a esteatose hepática dos camundongos C57BL/6, provavelmente devido à ativação PPAR-gama. / The study aimed to investigate the effects of telmisartan (a partial PPAR gamma agonist), losartan (a pure angiotensin II receptor blocker) and rosiglitazone (PPAR gamma agonist) in a mice model of metabolic syndrome (MetS). The targets of this study were blood pressure (BP), carbohydrate metabolism, insulin resistance, inflammation, white adipose tissue (WAT) and liver. Male C57BL/6 mice were studied over 17 weeks after being separated into two major groups according to diet: standard chow (SC, 10% fat, n = 10) or high-fat high-salt chow (HFHS, 60% fat, 7% salt, n = 40). In the last 5 weeks of the experiment, the HFHS group was divided into four groups (n = 10): untreated HFHS, ROSI (HFHS plus rosiglitazone), TELM (HFHS plus telmisartan), and LOS (HFHS plus losartan). The HFHS group had significantly greater body mass and BP, in addition to hyperinsulinemia with insulin resistance, hyperleptinemia, adipocyte hypertrophy and hepatic steatosis as well as increased inflammatory cytokine levels. Animals treated with telmisartan had body weights similar to the SC group, in addition to reversed insulin resistance, reduced hypertension, reduced adipocyte hypertrophy, ameliorates hepatic steatosis and decreased IL-6. Telmisartan increased PPARγ and adiponectin expression in white adipose tissue. Interestingly, the expression of UCP-1 in white adipose tissue was also increased by treatment with telmisartan. Losartan decreased BP but had smaller effects on metabolic parameters. The present model of diet-induced weight gain and hypertension in mice mimics human features of MetS. In this model, telmisartan enhances UCP-1 expression in WAT, prevented weight gain and ameliorates insulin sensitivity and hepatic steatosis in C57Bl/6 mice, probably due to PPAR gamma activation.

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Este trabalho teve como objetivo investigar os efeitos da telmisartana (agonista PPAR-gama parcial), losartana (puro bloqueador do receptor AT1 da angiotensina II) e rosiglitazona (agonista PPAR-gama) em modelo experimental de síndrome metabólica. Os alvos do estudo foram a pressão arterial, metabolismo de carboidratos, resistência insulínica, inflamação, tecido adiposo e fígado. Camundongos C57BL/6 (a partir de 3 meses de idade) foram alimentados com dieta padrão (SC, n = 10) ou dieta hiperlipídica rica em sal (HFHS, n = 40) por 12 semanas. Após esse tempo, os animais do grupo HFHS foram subdivididos em 4 grupos (n = 10): HFHS (sem tratamento), ROSI (HFHS tratado com rosiglitazona), TELM (HFHS tratado com telmisartana) e LOS (HFHS tratado com losartana) por 5 semanas. O grupo HFHS apresentou um significante ganho de peso e aumento da pressão arterial sistólica, hiperinsulinemia com resistência insulínica, hiperleptinemia, hipertrofia de adipócitos bem como um quadro de esteatose hepática e níveis aumentados da citocina inflamatória interleucina-6 (IL-6). Os animais tratados com telmisartana chegou ao final do experimento com massa corporal similar ao grupo SC, com reversão do quadro de resistência insulínica, com pressão arterial normal, adipócitos de tamanho normal e sem apresentar esteatose hepática. Além disso, o tratamento com telmisartana aumentou a expressão de PPARγ e adiponectina no tecido adiposo epididimal. A expressão da proteína desacopladora-1 (UCP-1) no tecido adiposo branco (TAB) também foi aumentada. O tratamento com losartana diminuiu a pressão arterial para valores normais, porém com menores efeitos nos parâmetros metabólicos dos animais. O presente modelo experimental de ganho de peso e hipertensão induzidos por dieta mimetiza a síndrome metabólica humana. Neste modelo, a telmisartana aumentou a expressão de UCP-1 no TAB, preveniu o ganho de peso e melhorou a sensibilidade à insulina e a esteatose hepática dos camundongos C57BL/6, provavelmente devido à ativação PPAR-gama. / The study aimed to investigate the effects of telmisartan (a partial PPAR gamma agonist), losartan (a pure angiotensin II receptor blocker) and rosiglitazone (PPAR gamma agonist) in a mice model of metabolic syndrome (MetS). The targets of this study were blood pressure (BP), carbohydrate metabolism, insulin resistance, inflammation, white adipose tissue (WAT) and liver. Male C57BL/6 mice were studied over 17 weeks after being separated into two major groups according to diet: standard chow (SC, 10% fat, n = 10) or high-fat high-salt chow (HFHS, 60% fat, 7% salt, n = 40). In the last 5 weeks of the experiment, the HFHS group was divided into four groups (n = 10): untreated HFHS, ROSI (HFHS plus rosiglitazone), TELM (HFHS plus telmisartan), and LOS (HFHS plus losartan). The HFHS group had significantly greater body mass and BP, in addition to hyperinsulinemia with insulin resistance, hyperleptinemia, adipocyte hypertrophy and hepatic steatosis as well as increased inflammatory cytokine levels. Animals treated with telmisartan had body weights similar to the SC group, in addition to reversed insulin resistance, reduced hypertension, reduced adipocyte hypertrophy, ameliorates hepatic steatosis and decreased IL-6. Telmisartan increased PPARγ and adiponectin expression in white adipose tissue. Interestingly, the expression of UCP-1 in white adipose tissue was also increased by treatment with telmisartan. Losartan decreased BP but had smaller effects on metabolic parameters. The present model of diet-induced weight gain and hypertension in mice mimics human features of MetS. In this model, telmisartan enhances UCP-1 expression in WAT, prevented weight gain and ameliorates insulin sensitivity and hepatic steatosis in C57Bl/6 mice, probably due to PPAR gamma activation.

L'infection au virus de l'hépatite B (VHB) est étroitement liée au métabolisme énergétique hépatique. La réplication du virus est contrôlée en principal par des facteurs de transcription et récepteurs nucléaires tels que PPARa, HNF4a et Foxül, impliqués dans ce métabolisme. Ainsi, la réplication du virus est augmentée par la privation de nutriments et le stress énergétique en modèles cellulaires, et par le jeûne, en modèles murins. PGC-la, un régulateur majeur de la réponse métabolique adaptative au jeûne, est impliqué dans l'augmentation de la transcription du VHB par son interaction avec plusieurs facteurs de transcription. Il est connu que le récepteur des acides biliaires, FXRa, qui est capable d'activer le promoteur de Core du VHB, est co-activaté par PGC-la. Un autre acteur important dans l'adaptation métabolique à la privation d'énergie est la protéine déacétylase SIRTl. Lorsqu'il est activé, SIRTl hépatique est capable de désacétyler et activer autant PGC-la que FXRa. Ces données nous ont amenés à émettre l'hypothèse que SIRTl pourrait coopérer avec FXRa et PGC-la pour augmenter la transcription du VHB. Dans un premier travail, nous avons donc étudié le rôle de la coopération de ces trois facteurs métaboliques dans la réplication du virus. Ça nous a permis de décrire un nouveau réseau métabolique, composé de FXRa, PGC-la et SIRTl, qui régule l'activité transcriptionnelle du VHB. Nous avons montré que SIRTl augmente l'activité du promoteur de Core par l'intermède d'autre facteurs, parmi lesquels, FXRa. Nous avons en outre observé que la fonction de déacétylase de SIRTl était nécessaire pour l'amplification de l'effet de FXRa sur VHB promoteur de Core. Une autre cible de SIRTl, connue pour son activité co-activatrice sur FXRa, est PGC-la. Grâce à une série d'expériences de surexpression et suppression, nous avons montré que non seulement la co-activation de FXRa par PGC-la est potentialisée par SIRTl, mais la présence de PGC-la est nécessaire pour l'effet de SIRTl sur l'activation du promoteur de Core VHB induite par FXRa. Ces données suggèrent que FXRa, PGC-la et SIRTl coopèrent dans la modulation de l'activité transcriptionnelle du promoteur de Core. Nous avons ensuite confirmé nos observations initiales et avons montré que l'activation de l'axe SIRTl/PGC-la/FXRa induit la transcription de l'ARN de VHB dans des lignées cellulaires d'origine hépatique et non-hépatique. Ces résultats renforcent l'idée que la réplication du VHB peut être modulée en fonction de l'état nutritionnel. Les rapports des études précédentes menées in vitro et sur des modèles animaux suggèrent que la transcription du VHB est contrôlée de la même manière que les gènes de la néoglucogenèse. Notre hypothèse a été que chez l'homme, la réplication du VHB montrerait des fluctuations diurnes, selon les périodes de la journée de jeûne et de réalimentation. Le but de la deuxième étude a été donc de déterminer si la charge viral du VHB plasmatique montre des variations importantes tout au long du nichthemeron chez les patients chroniquement infectés par VHB, avec une réplication virale active [etc...] / Hepatitis B virus (HBV) infection is tightly linked with hepatic fuel metabolism. HBV replication depends on the activity of several liver-enriched nuclear receptors and transcription factors, such as PPARa, HNF4a, and Fox01, involved in the metabolic adaptive response to fasting. In the first part of our work, we identified a metabolic subnetwork that enhances the activity of HBV core promoter. FXRa (NR1H4), PPAR gamma coactivator 1a and SIRT1, the members of this regulatory axis, cooperate to increase HBV transcription. The three molecules are themselves key factors of liver metabolism, linking HBV replication to complex metabolic cues, such as energy status and nutrient availability during the fasting-refeeding cycles. We then observed the existence of a circadian cycle of HBV replication in humans, underlining the role of nutrient availability in the modulation of HBV replication, previously predicted by experimental models. The second part of the work focused on the plasma cell-free nucleic acids as potential biomarkers in chronic viral hepatitis. Due to the multiple links between HBV replication and cellular factors involved in fuel metabolism, we hypothesized that plasma mRNAs corresponding to these factors may constitute potential biomarkers for chronic hepatitis B. We successfully detected more than 30 plasma mRNA sequences corresponding to enzymes, transporters, nuclear receptors and transcription factors involved in fatty acids synthesis and oxidation, cholesterol synthesis, transport and excretion, and energy sensing and expenditure. The circadian variation and the multiple correlations in the expression patterns of these plasma transcripts are similar to those previously described in cells both in vitro and in vivo. This suggests that cell- free mRNAs may provide a "virtual biopsy" of the transcriptional status of the organism. Moreover, we found significant differences in the plasma mRNA profiles of HBV carriers compared with healthy controls, similar to those found in experimental models of infection, suggesting that these transcripts may also serve as biomarkers of liver disease. Further research is warranted to shed new light on the complex relationship between HBV life cycle and host lipid-carbohydrate-fuel metabolism and may lead to the identification of both actionable targets in antiviral therapy, and putative biomarkers in chronic hepatitis B