News

8 November 2016

PhD student Yvonne won best poster award at EASyM

Yvonne Rozendaal, PhD student at the TU/e won the prize for the best poster at the EASyM conference in Berlin, Germany.

best-poster-award-easym

 

20 July 2016

Happy Summer!

A nice summer to all RESOLVE participants!

 

5 July 2016

PD position available

 

7 June 2016

Clara John about her research

Worldwide 1.7 billion people are affected by supernutrition and its repercussion, outpacing the global burden caused by malnutrition (Haslam and James 2005; Rosen and Spiegelman 2014). In many cases obesity (BMI > 30 kg/m2), a consequence of overnutrition, is accompanied by a disturbance of the cellular and systemic cholesterol homeostasis. According to the National Institute of Health, USA this accounts for one of the ten major risk factors for cardiovascular diseases. One of the causes leading to atherosclerosis involves impairments in vascular metabolism of cholesterol rich lipoproteins (Lewington, Whitlock et al. 2007; Ference, Yoo et al. 2012).

Due to the high metabolic activity of brown adipose tissue (BAT) and the possibility to induce the browning of different white adipose tissue-depots, the activation of BAT is considered as a therapeutic target to treat or prevent metabolic diseases. One of the main functions of BAT is the non-shivering thermogenesis (Cannon and Nedergaard 2004) leading to an increase in energy expenditure, which is paralleled by a robust stimulation of appetite and food intake including cholesterol. Whereas glucose and fatty acids serve as fuels for energy production and can be metabolized directly (Cannon and Nedergaard 2004; Bartelt, Bruns et al. 2011, an excess of cholesterol intake needs to be disposed by alternative routes to avoid the systemic accumulation of potentially cytotoxic cholesterol.

The underlying hypothesis of my work is that cold induced BAT-activation results in a dynamic adaption of vascular lipoprotein- as well as cellular sterol metabolism to maintain the general regulation of systemic cholesterol handling.

Our studies showed that the BAT-activation resulted in an increased HDL-turnover as well as reverse cholesterol transport (RCT), the movement of cholesterol from peripheral tissues back to the liver via HDL. Those results support the‘HDL-Flux-Hypothesis’proposed by Rader and Tall (2012). The hypothesis suggests that therapeutic interventions to promote HDL-mediated cholesterol efflux to the liver will reduce cardiovascular risk, regardless of whether it affects plasma cholesterol levels (Khera, Cuchel et al. 2011; Rohatgi, Khera et al. 2014). Additionally, we could observe that activated BAT induces the hepatobiliary disposal of cholesterol in form of bile acids.

These findings lead to the assumption that the activation of BAT contributes to preserve systemic cholesterol homeostasis. Future studies should therefore address the question of whether the activation of brown and beige adipocytes in humans could serve as a therapeutic target to prevent cardiovascular diseases.

 

29 February 2016

PhD student Dimitris Nasias about his research within the RESOLVE project

As a Phd candidate, my main interest is directed towards the understanding of the molecular networks underlying complex diseases. I am really keen on performing high throughput transcriptomic analyses in order to achieve global expression profiles and thus to identify their relevance in health and disease. Our research aims to monitor global changes in the gene expression profile of the liver and other tissues during the pathogenesis of the metabolic syndrome using the ApoE3L.CETP mouse as an experimental model. ApoE3Leiden.CETP mice display all the clinical features of the metabolic syndrome upon feeding a western type diet. The metabolic syndrome (MetS) is a group of clinical disorders including abdominal obesity, elevated blood pressure, loss of glycemic control, high triglycerides and low HDL cholesterol, whereas MetS patients are at increased risk for developing cardiovascular disease and type-2 diabetes. The molecular background of the MetS is poorly understood, whereas effective diagnostics and therapeutics are urgently needed. In our experiments, ApoE3L.CETP male mice are fed either a High Fat Diet (HFD) or Low Fat Diet (LFD) for 4, 8 and 12 weeks. RNA specimens from liver and other tissues are analyzed using Affymetrix microarrays followed by extensive bioinformatical analysis. The differentially expressed genes (HFD vs LFD for each time point) are annotated according to the Gene Ontology Classification. Further categorization of genes into pathways and networks of interactions give an insight into the biological significance of the differentially expressed genes and the affected biological processes. These data are combined with clinical measurements in the mice including body weight, total cholesterol and HDL levels, blood glucose levels and response in the glucose tolerance test. Moreover, we are investigating the role of FOXO1 in the pathogenesis of the MetS. FOXO1 is a transcription factor with important roles in glucose and lipid metabolism in the liver. More specifically, we are generating ApoE3Leiden.CETP mice expressing small interfering RNAs against the mouse FOXO1 gene in the liver using adeno-associated virus (AAV)-mediated gene transfer and use these mice for transcriptomics analyses. Given that FOXO1 activity is under negative control by insulin, this genetic intervention is anticipated to ameliorate the clinical phenotypes of MetS. Our ultimate goal is to identify key genes that are implicated in the pathogenesis of the MetS and utilize this information for the development of novel biomarkers and therapies.

 

 

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