Functional characterization of the PPAR targets ANGPTL4 and HILPDA in lipid metabolism
Mattijssen, F.B.J. - \ 2014
Wageningen University. Promotor(en): Sander Kersten. - Wageningen : Wageningen University - ISBN 9789461739087 - 193
lipidenmetabolisme - receptoren - genotype-voeding interactie - lipid metabolism - receptors - genotype nutrition interaction
The peroxisomal proliferator activator receptors (PPARs) are ligand-activated transcription factors that play important roles in the regulation of lipid metabolism. Three PPAR isoforms have been identified: PPARα, PPARβ/δ, and PPARγ. Each isoform has specific functions determined by their relative abundance in a cell as well as ligand specificity.
A highly sensitive PPAR target gene is represented by Angiopoietin-like 4 (ANGPTL4), which was discovered by two independent groups in 2000. ANGPTL4 is produced in a number of organs including liver and adipose tissue where its expression is governed by PPARα and PPARγ, respectively. Upon secretion, ANGPTL4 is cleaved into n- and c-terminal fragments that have divergent functions. nANGPTL4 is known to function as an inhibitor of lipoprotein lipase and hepatic lipase, whereas cANGPTL4 is involved in a number of processes including tumorigenesis and wound healing and is known to interact with integrins β1 and β5.
In this thesis we set out to expand our knowledge on the molecular function of ANGPTL4 in the regulation of lipid metabolism. We used a variety of animal models, cell culture, biochemical assays, and other functional measurements to zoom in on previously unexplored aspects of ANGPTL4.
Feeding mice deficient in ANGPLT4 a diet rich in long-chain saturated fatty acids elicited a complex phenotype and Angptl4-/- mice ultimately died from fibrinopurulent peritonitis. In contrast, the prevalence of the lethal phenotype was absent when the fat component of the high-fat diet was changed to medium-chain fatty acids, suggesting a role for increased chyle flow. Indeed, Angptl4-/- mice had dramatically enlarged mesenteric lymph nodes which contained numerous lipid laden macrophages. In vitro experiments showed that PPARβ/δ mediated induction of ANGPTL4 inhibits macrophage LPL. In the absence of ANGPTL4 there is increased lipid uptake in mesenteric lymph node macrophages, leading to ER stress and subsequent inflammatory response.
Additionally, Angptl4-/- mice gain more weight when fed a high-fat diet containing mainly unsaturated fatty acids. The increased body weight and adiposity was unrelated to food intake, activity, or energy expenditure. Remarkably, we observed increased lipid digestion in Angptl4-/- mice, which coincided with increased luminal lipase activity in the intestines of Angptl4-/- mice. Using biochemical assays we reveal that ANGPTL4 inhibits pancreatic lipase.
In the second part of this thesis we identified a novel PPAR target gene, hypoxia inducible lipid droplet associated (HILPDA). We observed HILPDA expression to be increased in liver slices exposed to a synthetic PPARα ligand. Additionally, oral dosing of similar ligand induced a marked increase in Hilpda expression in wild-type mice but not in Pparα-/- mice. PPAR mediated induction of Hilpda expression was found to be mediated by a conserved and functional PPRE located 1200 base pair or the transcription start site of HILPDA. Functional characterization of HILPDA in liver was performed via adeno-associated virus mediated overexpression. Interestingly, increased hepatic expression of HILPDA was associated with the development of a fatty liver, which could be attributes to a decrease in hepatic VLDL production.
HILPDA was also found to be highly expressed in both human and mouse adipose tissue, where its expression is under the control of PPARγ and β-adrenergic receptor. Moreover, adipose tissue HILPDA expression was increased with fasting and decreased with high-fat feeding. Despite the regulation of adipose tissue HILPDA by PPARγ, we observed no effect of HILPDA on adipogenesis. Furthermore, adipose tissue specific Hilpda knock-out mice showed no major metabolic perturbations upon fasting. However, overexpression of HILPDA in adipocytes significantly reduced the release of NEFA upon β-adrenergic receptor activation. Induction of HILPDA by β-adrenergic receptor stimulation may be part of feedback mechanism to regulate adipocyte lipolysis.
In conclusion, in thesis we have extended the current knowledge on the function of ANGPTL4. We show that ANGPTL4 serves as an important regulator in the process of lipid digestion and also in the protection of macrophages that reside in mesenteric lymph nodes that are exposed to high concentrations of lipid. HILPDA is a novel PPAR target that is involved in hepatic VLDL secretion and adipocyte lipolysis. Future research will focus on elucidating the mechanistic aspects of the regulation and function of HILPDA.
Nutrigenomics in human peripheral blood mononuclear cells : the effects of fatty acids on gene expression profiles of human circulating cells as assessed in human intervention studies
Bouwens, M. - \ 2009
Wageningen University. Promotor(en): Michael Muller, co-promotor(en): Lydia Afman. - [S.l. : S.n. - ISBN 9789085853275 - 128
genotype-voeding interactie - vetzuren - bloedcellen - genexpressie - visoliën - maatregel op voedingsgebied - nutrigenomica - genotype nutrition interaction - fatty acids - blood cells - gene expression - fish oils - nutritional intervention - nutrigenomics
Research on the effects of nutrition on the function and health of organs in the human body, such as liver and intestine, is difficult, because for this research organ tissue is needed. Since nutrition research is usually performed in healthy volunteers, this tissue is difficult to obtain. However, to find out what happens on cellular level we do need human cells. Because blood cells are transported through the entire body and are relatively easy to obtain, these cells are ideal to study the effect of nutrition on cellular level. For this research we used the latest molecular genomics techniques to study the activity (on/off switching, increase/decrease) of all our genes at once. We found that consumption of different types of fat, both directly after consumption and after continued intake, changed the activity of specific groups of genes in these cells. With this research we have shown that the subtle effects of nutrition can be studied using nutrigenomics techniques in humans by using blood cells.
Public acceptance of nutrigenomics-based personalised nutrition : exploring the future with experts and consumers
Ronteltap, A. - \ 2008
Wageningen University. Promotor(en): Hans van Trijp, co-promotor(en): Reint-Jan Renes. - [S.l.] : S.n. - ISBN 9789085049982 - 165
houding van consumenten - genotype-voeding interactie - voeding - consumentengedrag - innovatie adoptie - marketing - consumenten - consumentenvoorkeuren - deskundigen - voedingsmiddelen - nutrigenomica - consumer attitudes - genotype nutrition interaction - nutrition - consumer behaviour - innovation adoption - consumers - consumer preferences - experts - foods - nutrigenomics
Nutrigenomics is a recent discipline within nutrition sciences that aims at understanding how food components influence health status by affecting gene expression to eventually help maintain health and prevent disease. Nutrigenomics science has a potential consumer application in the form of so-called personalised nutrition: tailored dietary advice or even personalised food products that help consumers to select foods that are optimally aligned with their genetic constitution. However, due to the fact that nutrigenomics is an emerging science and personalised nutrition is still at an early stage of development, the views of both expert and lay stakeholders on the meaning, potential, and acceptability of personalised nutrition may still be divergent and developing. This dissertation takes up the challenge of understanding and anticipating public acceptance of nutrigenomics-based personalised nutrition. It aims to answer the central research question: What determines public acceptance of nutrigenomics-based personalised nutrition? For this purpose, three lines of research are
explored: development of a conceptual research framework from existing literature, expert views on the future of personalised nutrition, and consumer evaluations of different scenarios under which personalised nutrition might enter the market place.
The thesis’ theoretical contribution lies in an in-depth analysis of the concept of personalisation using marketing and consumer behaviour literature (chapter 2), and the development of a conceptual framework for consumer acceptance of food innovations (chapter 3). Empirically, results from a consumer study within a representative sample of Dutch consumers (chapter 5) reveal that freedom of choice, clear advantages, ease of applying personalised nutrition, and consensus among experts are important factors in enhancing consumer acceptance. However, the research in this thesis also shows that experts have not yet reached the necessary consensus on the scope and potential of nutrigenomics (chapter 4), and that experts do not expect that it will be easy for consumers to incorporate personalised nutrition into their daily lives (chapter 6). These, and other, issues can serve as inspiration for future research, as well as the further refinement of the generic framework for consumer acceptance of food innovations.
In conclusion, this thesis contributes to a better understanding of how public acceptance of the scientific innovation of nutrigenomics-based personalised nutrition comes about. It shows how issues critical for the further development of such an emerging science and the innovations arising from it can be systematically identified and addressed.
|Eten volgens je genenpakket: gezond dik zijn, het kan, al zullen niet alle gezondheidsvoorlichters daar blij mee zijn
Müller, M.R. - \ 2008
Voeding Nu 10 (2008)4. - ISSN 1389-7608 - p. 18 - 19.
genotype-voeding interactie - voedingsmiddelen - genetica - individuele voeding - ziektepreventie - metabolisme - genen - voedselconsumptie - genexpressieanalyse - nutrigenomica - genotype nutrition interaction - foods - genetics - individual feeding - disease prevention - metabolism - genes - food consumption - genomics - nutrigenomics
Hoe lang duurt het nog voordat we aan de hand van een individueel genenpakket boodschappen kunnen gaan doen; dat we in de winkel als 'geautomatiseerd' de keuze voor de beste voeding voor onszelf kunnen maken, ter voorkoming van ziekten? Volgens hoogleraar voedingsmetabolisme en genomics Michael Müller van Wageningen Universiteit, lopen bedrijven die nu al dieetadvies geven aan de hand van genentests te ver voor de muziek uit
|Nutrigenomics, nieuwe mogelijkheden voor de voedingswetenschap
Kok, F.J. ; Schouten, E.G. - \ 2001
Voeding Nu 2 (2001). - ISSN 1389-7608 - p. 16 - 17.
merkergenen - genetische merkers - voedselwetenschappen - voedingsmiddelen - voedselanalyse - moleculaire biologie - interacties - genotype-voeding interactie - metabolisme - voedingsonderzoek bij de mens - voedselveiligheid - ziektepreventie - marker genes - genetic markers - food sciences - foods - food analysis - molecular biology - interactions - genotype nutrition interaction - metabolism - human nutrition research - food safety - disease prevention
Men verwacht dat het genomics-onderzoek ons inzicht in de werkingsmechanismen van voeding zal verbeteren. Het 'Centre for Human NutriGenomics' is een breed samenwerkingsverband tussen Wageningen Universiteit, Rikilt, Plant Research International, TNO Voeding, Universiteit Maastricht en het RIVM (http:www.nutrigenomics.nl)