1,721,063 research outputs found
EXAMINING THE DIVERSE CONTRIBUTIONS OF EL TO SYSTEMIC LIPID METABOLISM
Full text linkLa Lipasi Endoteliale (EL) è l’ultimo membro identificato della famiglia delle lipasi plasmatiche dei trigliceridi (plasma triglyceride lipase). EL ha una maggior specificità per i fosfolipidi (PL) che trigliceridi (TG) ed è un enzima chiave nella regolazione dei livelli di HDL sia in vitro che in vivo. Studi più recenti hanno indicato che EL è in anche grado di promuovere il catabolismo delle lipoproteine contenenti apoB. Nell’uomo, varianti nel gene che codifica per EL, sono state associate a più elevati livelli di colesterolo HDL ma sorprendentemente ciò non si traduce in un ridotto rischio cardiovascolare. Studi clinici hanno evidenziato che la concentrazione e attività di EL sono positivamente associate alla severità dei tratti tipici della sindrome metabolica come indice di massa corporea, obesità centrale, infiammazione, insulino resistenza e profilo lipoproteico più aterogenico. Quale sia il nesso causale di questa associazione non è noto e ad oggi non è possibile stabilire se elevati livelli di EL siano alla base dell’eziologia del profilo osservato o se, al contrario, siano un tratto secondario. Scopo di questa tesi è di stabilire quale sia il ruolo di EL nel metabolismo delle lipoproteine ricche in trigliceridi (TRL) e di investigare la relazione tra attività di EL, metabolismo lipidico epatico e sviluppo dei tratti caratteristici della sindrome metabolica in vivo. Al fine di poter comparare non solo la severità ma anche il tempo di insorgenza della sindrome metabolica, in presenza o assenza di EL, sono stati utilizzati topi controllo (wild type, WT) e topi con deficit di EL (EL-KO), sottoposti ad una dieta ricca di grassi a lungo termine. I risultati hanno dimostrato che i topi EL-KO accumulano significativamente più peso rispetto ai WT, sviluppano una più severa intolleranza al glucosio, e uno stato metainfiammatorio. La comparsa di questi tratti è accompagnata da una severa dislipidemia, ancora una volta più marcata nei topi EL-KO rispetto ai WT. La differenza più significativa, tuttavia, è lo sproporzionato aumento dei livelli di TG in risposta alla dieta. All’origine di questo fenotipo vi è l’accumulo di lipoproteine post-prandiali ricche di TG.
Esperimenti cinetici in vivo hanno dimostrato che la clearance di TRL radiomarcate è molto ridotta nei topi EL-KO e questo fenomeno è dovuto a una ridotta lipolisi, mentre la secrezione epatica di TG non è affetta. Quando l’attività di EL nei confronti delle TRL marcate è stata testata in vitro, è emerso che EL potrebbe fungere da facilitatore dell’attività della lipasi lipoproteica (LPL). Di conseguenza, EL potrebbe rivestire un ruolo importante nel ridurre I livelli di TG nel contesto dell’iperlipemia postprandiale e questo effetto potrebbe essere mediato sia da un’attività lipolitica diretta, sia dalla facilitazione dell’attività lipolitica di LPL. Infine, la valutazione della funzionalità epatica ha rivelato che i topi EL-KO sviluppano una franca steatosi. La capacità del fegato di captare gli acidi grassi derivanti dai TG, è ridotta nei topi con deficit di EL ed è stato osservato un parallelo aumento dei livelli di espressione di geni coinvolti nella lipogenesi e una drammatica alterazione del contenuto di acidi grassi. In conclusione, i dati raccolti in questa tesi supportano l’ipotesi che EL sia essenziale per un’efficiente clearance delle TRL e, in sua assenza, via sia un ridotto flusso di acidi grassi al fegato. Ciò indurrebbe un aumento compensatorio della lipogenesi e potrebbe ulteriormente contribuire all’insorgenza di obesità e insulino resistenza.Endothelial Lipase (EL) is the most recently identified member of the plasma triglyceride lipase family. EL has a higher specificity for Phospholipids (PL) compared to triglycerides (TG) and has been shown to be a major regulator of HDL-C levels both in vitro and in vivo. More recent data showed that EL also promotes the catabolism of apoB-containing lipoproteins. In humans, genetic variants for EL are associated with increased HDL-C levels but these changes do not translate into a reduction in cardiovascular disease risk. Early clinical
studies demonstrated a strong correlation between EL mass and several traits of metabolic syndrome such as body mass index (BMI), visceral adiposity, inflammation, insulin resistance and atherogenic lipoprotein levels. The causal relationship linking EL to one of multiple of these traits is still unknown. To
date, whether increased EL levels may be causal to the observed phenotype or a secondary outcome has not been established.
The aim of this thesis is to assess the role of EL in TG-rich lipoprotein (TRL) metabolism and to investigate the relationship between EL activity, hepatic lipid metabolism and the development of key traits of metabolic syndrome in vivo. In order to compare the onset and severity of metabolic syndrome traits in the presence or absence of EL activity, WT and EL deficient mice (EL-KO) were chronically fed a high fat diet. Results demonstrated that EL deficient mice gained significantly more weight and they developed a more severe
glucose intolerance and meta-inflammatory state. The appearance of these traits was accompanied by a severe dyslipidemia that was once again more pronounced in EL-KO mice, compared to WT. The most evident difference between EL-deficient mice and control group was the disproportioned diet-induced
increase in TG. This phenotype originated from accumulation of postprandial TG-rich lipoproteins. In vivo kinetic experiments demonstrated that the lipolytic clearance of TG-labeled TRL was significantly impaired in EL-KO mice without any effect on TG secretion. The in vitro determination of EL activity towards radiolabeled-TRLs suggested that EL may function as a Lipoprotein Lipase (LPL) activity enhancer. As a consequence, EL may have a major role in reducing TG levels during postprandial hyperlipemia and this
effect may be mediated by both direct lipolysis and facilitation of LPL. Finally, the assessment of liver function revealed that the dietary treatment induced severe steatosis in EL-KO mice. Consistent with reduced lipolysis, the TG-derived FA uptake was impaired in EL-KO mice and this was associated with the upregulation of lipogenic genes and the development of abnormalities in the FA composition.
In conclusion, data from this thesis support a model by which EL is required for efficient triglyceride-rich lipoprotein clearance and the absence of this function impairs hepatic fat intake and results in compensatory de novo lipogenesis, which may contribute to systemic obesity and insulin resistance
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
HDL and cholesterol handling in the brain
No full textCholesterol is an essential component of both the peripheral nervous system and central nervous system (CNS) of mammals. Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools of cholesterol in the body, but a small fraction can be taken up from the circulation as 27-hydroxycholesterol, or via the scavenger receptor class B type I. Glial cells synthesize native high-density lipoprotein (HDL)-like particles, which are remodelled by enzymes and lipid transfer proteins, presumably as it occurs in plasma. The major apolipoprotein constituent of HDL in the CNS is apolipoprotein E, which is produced by astrocytes and microglia. Apolipoprotein A-I, the major protein component of plasma HDL, is not synthesized in the CNS, but can enter and become a component of CNS lipoproteins. Low HDL-C levels have been shown to be associated with cognitive impairment and various neurodegenerative diseases. On the contrary, no clear association with brain disorders has been shown in genetic HDL defects, with the exception of Tangier disease. Mutations in a wide variety of lipid handling genes can result in human diseases, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking
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