Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity
Bosma, M. ; Dapito, D.H. ; Drosatos-Tampakaki, Z. ; Huiping-Son, N. ; Huang, L.S. ; Kersten, A.H. ; Drosatos, K. ; Goldberg, I.J. - \ 2014
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1841 (2014)12. - ISSN 1388-1981 - p. 1648 - 1655.
hormone-sensitive lipase - activated receptor-gamma - skeletal-muscle - insulin-resistance - cardiac myocytes - transgenic mice - cell-death - lipid-metabolism - heart-failure - ppar-alpha
We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPAR gamma, ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (ElF2a). Both ACSL1 and PPAR gamma adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterffied free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress. (C) 2014 Elsevier B.V. All rights reserved.
Prion disease tempo determined by host-dependent substrate reduction
Mays, C.E. ; Kim, C. ; Haldiman, T. ; Merwe, J. v.d.; Lau, A. ; Yang, J. ; Grams, J. ; Bari, M.A. Di; Nonno, R. ; Telling, G.C. ; Kong, Q. ; Langeveld, J.P.M. ; McKenzie, D. ; Westaway, D. ; Safar, J.G. - \ 2014
The Journal of Clinical Investigation 124 (2014)2. - ISSN 0021-9738 - p. 847 - 858.
chronic wasting disease - transgenic mice - cyclic amplification - cultured-cells - sheep scrapie - prpsc levels - protein - propagation - immunoassay - strains
The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains
Enhanced virulence of sheep-passaged bovine spongiform encephalopathy agent is revealed by decreased polymorphism barriers in prion protein conversions studies.
Priem, J. ; Langeveld, J.P.M. ; Keulen, L.J.M. van; Zijderveld, F.G. van; Andreoletti, O. ; Bossers, A. - \ 2014
Journal of Virology 88 (2014)5. - ISSN 0022-538X - p. 2903 - 2912.
misfolding cyclic amplification - in-vitro amplification - cell-free conversion - susceptibility-linked polymorphisms - transgenic mice - natural scrapie - classical scrapie - oral-transmission - infectious prions - resistant forms
Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to small ruminants (sheep and goats) with certain prion protein (PrP) genotypes. Polymorphisms in PrP of both the host and donor influence the transmission efficiency of transmissible spongiform encephalopathies (TSEs) in general. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species in vitro using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known in vivo transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie- and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called “resistant” sheep ARR variant).
Role of the Goat K222-PrPC Polymorphic variant in Prion Infection Resistance
Aguilar-Calvo, P. ; Espinosa, J.C. ; Pintado, B. ; Gutiérrez-Adán, A. ; Alamilo, E. ; Miranda, A. ; Prieto, I. ; Bossers, A. ; Andreoletti, O. ; Torres, J.M. - \ 2014
Journal of Virology 88 (2014)5. - ISSN 0022-538X - p. 2670 - 2676.
bovine spongiform encephalopathy - protein gene polymorphisms - caprine prp gene - natural scrapie - classical scrapie - transgenic mice - sheep - identification - association - genotype
The prion protein-encoding gene (prnp) strongly influences the susceptibility of small ruminants to transmissible spongiform encephalopathies (TSEs). Hence, selective breeding programs have been implemented to increase sheep resistance to scrapie. For goats, epidemiological and experimental studies have provided some association between certain polymorphisms of the cellular prion protein (PrPC) and resistance to TSEs. Among them, the Q/K polymorphism at PrPC codon 222 (Q/K222) yielded the most promising results. In this work, we investigated the individual effects of the K222-PrPC variant on the resistance/susceptibility of goats to TSEs. For that purpose, we generated two transgenic mouse lines, expressing either the Q222 (wild type) or K222 variant of goat PrPC. Both mouse lines were challenged intracerebrally with a panel of TSE isolates. Transgenic mice expressing the wild-type (Q222) allele were fully susceptible to infection with all tested isolates, whereas transgenic mice expressing similar levels of the K222 allele were resistant to all goat scrapie and cattle BSE isolates but not to goat BSE isolates. Finally, heterozygous K/Q222 mice displayed a reduced susceptibility to the tested panel of scrapie isolates. These results demonstrate a highly protective effect of the K222 variant against a broad panel of different prion isolates and further reinforce the argument supporting the use of this variant in breeding programs to control TSEs in goat herds. IMPORTANCE The objective of this study was to determine the role of the K222 variant of the prion protein (PrP) in the susceptibility/resistance of goats to transmissible spongiform encephalopathies (TSEs). Results showed that transgenic mice expressing the goat K222-PrP polymorphic variant are resistant to scrapie and bovine spongiform encephalopathy (BSE) agents. This protective effect was also observed in heterozygous Q/K222 animals. Therefore, the single amino acid exchange from Q to K at codon 222 of the cellular prion protein provides resistance against TSEs. All the results presented here support the view that the K222 polymorphic variant is a good candidate for selective breeding programs to control and eradicate scrapie in goat herds.
Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis
Guen, L. ; Karpanen, T. ; Schulte, D. ; Harris, N.C. ; Koltowska, K. ; Roukens, G. ; Bower, N.I. ; Impel, A. van; Stacker, S.A. ; Achen, M.G. ; Schulte-Merker, S. ; Hogan, B.M. - \ 2014
Development 141 (2014). - ISSN 0950-1991 - p. 1239 - 1249.
growth-factor receptor-3 - lymphatic endothelial-cells - vascular development - factor-c - missense mutations - primary lymphedema - network formation - transgenic mice - in-vivo - zebrafish
The VEGFC/VEGFR3 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from pre-existing vasculature) during embryonic development, tissue regeneration and tumor progression. The recently identified secreted protein CCBE1 is indispensible for lymphangiogenesis during development. The role of CCBE1 orthologs is highly conserved in zebrafish, mice and humans with mutations in CCBE1 causing generalized lymphatic dysplasia and lymphedema (Hennekam syndrome). To date, the mechanism by which CCBE1 acts remains unknown. Here, we find that ccbe1 genetically interacts with both vegfc and vegfr3 in zebrafish. In the embryo, phenotypes driven by increased Vegfc are suppressed in the absence of Ccbe1, and Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression. Moreover, Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1. Finally, CCBE1 is capable of upregulating the levels of fully processed, mature VEGFC in vitro and the overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes in zebrafish. Taken together, these data identify Ccbe1 as a crucial component of the Vegfc/Vegfr3 pathway in the embryo.
Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development
Georgiadi, A. ; Wang, Y. ; Stienstra, R. ; Tjeerdema, N. ; Janssen, A. ; Stalenhoef, A. ; Vliet, A. van der; Roos, J.A. de; Tamsma, J.T. ; Smit, J.W. ; Tan, N.S. ; Müller, M.R. ; Rensen, P.C. ; Kersten, A.H. - \ 2013
Arteriosclerosis Thrombosis and Vascular Biology 33 (2013)7. - ISSN 1079-5642 - p. 1529 - 1537.
low-density-lipoprotein - mouse peritoneal-macrophages - foam cell-formation - transgenic mice - lipase - angptl4 - expression - gene - hyperlipoproteinemia - hyperlipidemia
Objective—Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. Approach and Results—Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P
Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
Haldiman, T. ; Kim, C. ; Cohen, Y. ; Chen, W. ; Blevins, J. ; Qing, L. ; Cohen, M.L. ; Langeveld, J.P.M. ; Telling, G.C. ; Kong, Q. ; Safar, J.G. - \ 2013
Journal of Biological Chemistry 288 (2013). - ISSN 0021-9258 - p. 29846 - 29861.
creutzfeldt-jakob-disease - transmissible mink encephalopathy - chronic wasting disease - dependent immunoassay - strain variation - transgenic mice - molecular-basis - protein - scrapie - classification
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). The protein misfolding cyclic amplification (PMCA) replicates each of the PrPSc particle types independently, and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sCJD PrPSc is not a single conformational entity, but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers.
Chronic Wasting Disease in Bank Voles: Characterisation of the Shortest Incubation Time Model for Prion Diseases
Bari, M.A. Di; Nonno, R. ; Castilla, J. ; Augostino, C. D'; Pirisinu, L. ; Riccardi, G. ; Conte, M. ; Richt, J.A. ; Kunkle, R. ; Langeveld, J.P.M. ; Vaccari, G. ; Agrimi, U. - \ 2013
PLoS Pathogens 9 (2013)3. - ISSN 1553-7366
chromatography-mass spectrometry - misfolding cyclic amplification - creutzfeldt-jakob-disease - cervus-elaphus-nelsoni - in-vitro generation - transgenic mice - spongiform encephalopathy - mule deer - species-barrier - protein allotypes
In order to assess the susceptibility of bank voles to chronic wasting disease (CWD), we inoculated voles carrying isoleucine or methionine at codon 109 (Bv109I and Bv109M, respectively) with CWD isolates from elk, mule deer and white-tailed deer. Efficient transmission rate (100%) was observed with mean survival times ranging from 156 to 281 days post inoculation. Subsequent passages in Bv109I allowed us to isolate from all CWD sources the same vole-adapted CWD strain (Bv109ICWD), typified by unprecedented short incubation times of 25–28 days and survival times of ~35 days. Neuropathological and molecular characterisation of Bv109ICWD showed that the classical features of mammalian prion diseases were all recapitulated in less than one month after intracerebral inoculation. Bv109ICWD was characterised by a mild and discrete distribution of spongiosis and relatively low levels of protease-resistant PrPSc (PrPres) in the same brain regions. Despite the low PrPres levels and the short time lapse available for its accumulation, end-point titration revealed that brains from terminally-ill voles contained up to 108,4 i.c. ID50 infectious units per gram. Bv109ICWD was efficiently replicated by protein misfolding cyclic amplification (PMCA) and the infectivity faithfully generated in vitro, as demonstrated by the preservation of the peculiar Bv109ICWD strain features on re-isolation in Bv109I. Overall, we provide evidence that the same CWD strain was isolated in Bv109I from the three-cervid species. Bv109ICWD showed unique characteristics of “virulence”, low PrPres accumulation and high infectivity, thus providing exceptional opportunities to improve basic knowledge of the relationship between PrPSc, neurodegeneration and infectivity.
Lipidomics reveals multiple pathway effects of a multi components preparation on lipd biochemistry in ApoeE*3Leiden.CETP mice
Wei, H. ; Hu, C. ; Wang, M. ; Hoek, A.M. van den; Reijmers, T.H. ; Wopereis, S. ; Bouwman, J. ; Ramaker, R. ; Korthout, H.A.A.J. ; Vennik, M. ; Hankemeier, T. ; Havekes, L.M. ; Witkamp, R.F. ; Verheij, E.R. ; Xu, G. ; Greef, J. de - \ 2012
PLoS One 7 (2012)1. - ISSN 1932-6203
cholesteryl ester transfer - systems biology - apoe-asterisk-3-leiden.cetp mice - aggravates atherosclerosis - overweight patients - chinese medicine - weight-reduction - transfer protein - hdl-cholesterol - transgenic mice
Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. Methodology/Principal Findings: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p <0.001), CETP levels (-31%, p
Detailed transcriptomics analysis of the effect of dietary fatty acids on gene expression in the heart
Georgiadi, A. ; Boekschoten, M.V. ; Muller, M.R. ; Kersten, A.H. - \ 2012
Physiological genomics 44 (2012). - ISSN 1094-8341 - p. 352 - 361.
proliferator-activated receptors - ppar-alpha - heme oxygenase-1 - lipoprotein-lipase - cardiac myocytes - lipid-metabolism - transgenic mice - rat-heart - triglycerides - eicosanoids
Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single oral dose of synthetic triglycerides composed of one single fatty acid. Hearts were collected 6 h thereafter and used for whole genome gene expression profiling. Experiments were conducted in wild-type and peroxisome proliferator-activated receptor (PPAR)a-/- mice to allow exploration of the specific contribution of PPARa. It was found that: 1) C18:3 had the most pronounced effect on cardiac gene expression. 2) The largest similarity in gene regulation was observed between C18:2 and C18:3. Large similarity was also observed between PPARa agonist Wy14643 and C22:6. 3) Many genes were regulated by one particular treatment only. Genes regulated by one particular treatment showed large functional divergence. 4) The majority of genes responding to fatty acid treatment were regulated in a PPARa-dependent manner, emphasizing the importance of PPARa in mediating transcriptional regulation by fatty acids in the heart. 5) Several genes were robustly regulated by all or many of the fatty acids studied, mostly representing well-described targets of PPARs (e.g., Acot1, Angptl4, Ucp3) but also including Zbtb16/PLZF, a transcription factor crucial for natural killer T cell function. 6) Deletion and activation of PPARa had a major effect on expression of numerous genes involved in metabolism and immunity. Our analysis demonstrates the marked impact of dietary fatty acids on gene regulation in the heart via PPARa
Differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and CH1641 scrapie
Jacobs, J.G. ; Sauer, M. ; Keulen, L.J.M. van; Tang, Y. ; Bossers, A. ; Langeveld, J.P.M. - \ 2011
Journal of General Virology 92 (2011)1. - ISSN 0022-1317 - p. 222 - 232.
creutzfeldt-jakob-disease - abnormal prion protein - natural sheep scrapie - monoclonal-antibodies - molecular analysis - atypical scrapie - prp(d) accumulation - transgenic mice - infected sheep - bse
With increased awareness of the diversity of transmissible spongiform encephalopathy (TSE) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. Exposure to bovine spongiform encephalopathy (BSE) has been associated with the human TSE, variant Creutzfeldt–Jakob disease, emphasizing the necessity in distinguishing low-risk TSE types from BSE. TSE type discrimination in ruminants such as cattle, sheep, goats and deer, requires the application of several prion protein (PrP)-specific antibodies in parallel immunochemical tests on brain homogenates or tissue sections from infected animals. This study uses in a single incubation step, three PrP-specific antibodies and fluorescent Alexa dye-labelled anti-mouse Fabs on a Western blot. The usual amount of brain tissue needed is 0.5 mg. This multiplex application of antibodies directed towards three different PrP epitopes enabled differential diagnosis of all established main features of classical scrapie, BSE and Nor98-like scrapie in sheep and goats, as well as the currently known BSE types C, H and L in cattle. Moreover, due to an antibody-dependent dual PrP-banding pattern, for the first time CH1641 scrapie of sheep can be reliably discriminated from the other TSE isolate types in sheep.
A new method for the Characterization of Strain-Specific Conformational Stability of Protease-Sensitive and Protease Resistant PrPSc
Pirisinu, L. ; Bari, M. Di; Marcon, S. ; Vaccari, G. ; Agostino, C. D'; Fazzi, P. ; Esposito, E. ; Cardone, F. ; Langeveld, J.P.M. ; Agrimi, U. ; Nonno, R. - \ 2010
PLoS One 5 (2010). - ISSN 1932-6203 - 12 p.
bovine spongiform encephalopathy - creutzfeldt-jakob-disease - scrapie prion protein - transgenic mice - molecular-basis - sheep scrapie - in-vitro - conversion - ovine - susceptibility
Although proteinacious in nature, prions exist as strains with specific self-perpetuating biological properties. Prion strains are thought to be associated with different conformers of PrPSc, a disease-associated isoform of the host-encoded cellular protein (PrPC). Molecular strain typing approaches have been developed which rely on the characterization of protease-resistant PrPSc. However, PrPSc is composed not only of protease-resistant but also of protease-sensitive isoforms. The aim of this work was to develop a protocol for the molecular characterization of both, protease-resistant and protease-sensitive PrPSc aggregates. We first set up experimental conditions which allowed the most advantageous separation of PrPC and PrPSc by means of differential centrifugation. The conformational solubility and stability assay (CSSA) was then developed by measuring PrPSc solubility as a function of increased exposure to GdnHCl. Brain homogenates from voles infected with human and sheep prion isolates were analysed by CSSA and showed strain-specific conformational stabilities, with mean [GdnHCl]1/2 values ranging from 1.6 M for MM2 sCJD to 2.1 for scrapie and to 2.8 M for MM1/MV1 sCJD and E200K gCJD. Interestingly, the rank order of [GdnHCl]1/2 values observed in the human and sheep isolates used as inocula closely matched those found following transmission in voles, being MM1 sCJD the most resistant (3.3 M), followed by sheep scrapie (2.2 M) and by MM2 sCJD (1.6 M). In order to test the ability of CSSA to characterise protease-sensitive PrPSc, we analysed sheep isolates of Nor98 and compared them to classical scrapie isolates. In Nor98, insoluble PrPSc aggregates were mainly protease-sensitive and showed a conformational stability much lower than in classical scrapie. Our results show that CSSA is able to reveal strain-specified PrPSc conformational stabilities of protease-resistant and protease-sensitive PrPSc and that it is a valuable tool for strain typing in natural hosts, such as humans and sheep.
Mitochondrial (dys)function in adipocyte (de)-differentiation and systemic metabolic alterations
Pauw, A. de; Tejerina, S. ; Raes, M. ; Keijer, J. ; Arnould, T. - \ 2009
American Journal of Pathology 175 (2009)3. - ISSN 0002-9440 - p. 927 - 939.
white adipose-tissue - active antiretroviral therapy - polyunsaturated fatty-acids - receptor corepressor rip140 - element-binding protein - necrosis-factor-alpha - insulin-resistance - transgenic mice - uncoupling protein-3 - 3t3-l1 adipocytes
In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria
Genome-Wide mRNA Expression Analysis of Hepatic Adaptation to High-Fat Diets Reveals Switch from an Inflammatory to Steatotic Transcriptional Program
Radonjic, M. ; Haan, J.R. de; Erk, M.J. van; Willems van Dijk, K. ; Berg, S.A.A. van den; Groot, P.J. de; Müller, M.R. ; Ommen, B. van - \ 2009
PLoS One 4 (2009)8. - ISSN 1932-6203
nf-kappa-b - proliferator-activated receptors - gene-expression - insulin-resistance - transgenic mice - deficient mice - ppar-gamma - 15-deoxy-delta(12,14)-prostaglandin j(2) - apoe-asterisk-3leiden mice - molecular-mechanisms
Background- Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood. Principal Findings - To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-¿B, NEMO, Akt, PPAR¿ and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels. Conclusions - The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-¿B and PPAR¿ regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies
Molecular discrimination of atypical bovine spongiform encephalopathy strains from a geographical region spanning a wide area in Europe
Jacobs, J.G. ; Langeveld, J.P.M. ; Biacabe, A.G. ; Acutis, P.L. ; Polak, M.P. ; Gavier-Widen, D. ; Buschmann, A. ; Caramelli, M. ; Casalone, C. ; Mazza, M. ; Groschup, M. ; Erkens, J.H.F. ; Davidse, A. ; Zijderveld, F.G. van; Baron, T. - \ 2007
Journal of Clinical Microbiology 45 (2007)6. - ISSN 0095-1137 - p. 1821 - 1829.
transmissible mink encephalopathy - creutzfeldt-jakob-disease - abnormal prion protein - transgenic mice - monoclonal-antibodies - messenger-rna - scrapie agent - n-glycosidase - brain-stem - prp gene
Transmissible spongiform encephalopathy strains can be differentiated by their behavior in bioassays and by molecular analyses of the disease-associated prion protein (PrP) in a posttranslationally transformed conformation (PrPSc). Until recently, isolates from cases of bovine spongiform encephalopathy (BSE) appeared to be very homogeneous. However, a limited number of atypical BSE isolates have recently been identified upon analyses of the disease-associated proteinase K (PK) resistance-associated moiety of PrPSc (Prp(res)), suggesting the existence of at least two additional BSE PrPres variants. These are defined here as the H type and the L type, according to the higher and lower positions of the nonglycosylated PrPres band in Western blots, respectively, compared to the position of the band in classical BSE (C-type) isolates. These molecular Prpres variants, which originated from six different European countries, were investigated together. In addition to the migration properties and glycosylation profiles (glycoprofiles), the H- and L-type isolates exhibited enhanced PK sensitivities at pH 8 compared to those of the C-type isolates. Moreover, H-type BSE isolates exhibited differences in the binding of antibodies specific for N- and more C-terminal PrP regions and principally contained two aglycosylated PrPres moieties which can both be glycosylated and which is thus indicative of the existence of two PrPres, populations or intermediate cleavage sites. These properties appear to be consistent within each BSE type and independent of the geographical origin, suggesting the existence of different BSE strains in cattle. The choice of three antibodies and the application of two pHs during the digestion of brain homogenates provide practical and diverse tools for the discriminative detection of these three molecular BSE types and might assist with the recognition of other variants.
The Fasting-induced Adipose Factor/Angiopoietin-like Protein 4 Is Physically Associated with Lipoproteins and Governs Plasma Lipid Levels and Adiposity
Mandard, S.J. ; Zandbergen, F.J. ; Straten, E. van; Wahli, W. ; Kuipers, F. ; Müller, M.R. ; Kersten, A.H. - \ 2006
Journal of Biological Chemistry 281 (2006)2. - ISSN 0021-9258 - p. 934 - 944.
angiopoietin-like protein-4 - high-density-lipoprotein - acylation stimulating protein - severe hypertriglyceridemia - triglyceride clearance - endothelial lipase - insulin-resistance - transgenic mice - target gene - expression
Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.
Effects of central infusion and immunoneutralization of growth hormone on the timing of puberty and plasma leptin levels in the female rat
Zeinoaldini, S. ; Swarts, J.J.M. ; Heijning, B.J.M. van de - \ 2006
Regulatory Peptides 134 (2006)2-3. - ISSN 0167-0115 - p. 158 - 163.
gene-expression - serum leptin - metabolic signal - body-composition - transgenic mice - adipose-tissue - messenger-rna - food-intake - gh gene - insulin
Growth hormone (GH) levels increase during puberty though its role in puberty onset is still unclear. An interaction is suggested between GH and leptin, as triggering factor of puberty. To evaluate the role of GH on the timing of puberty and its relation with leptin, we centrally administered recombinant human GH (rhGH; 1 ¿g/day) to normally fed or food-restricted (FR) prepubertal female rats, and monitored time of vaginal opening (VO). Median time of VO was equally postponed in FR animals and in normally fed rhGH-infused rats: median time of VO was respectively 35 and 34 vs. 27 d. Central infusion of rhGH in FR rats partially restored the delay in VO. Plasma leptin levels were increased in rhGH-infused animals, normally fed or FR. Centrally infused anti-rat GH (0.6 ¿g/day) did not affect plasma leptin levels, but advanced median time of VO (25 vs. 28 d) in pair-fed female rats but not in ad lib-fed animals. The effects of the centrally infused compounds appear to depend on the dietary regime imposed on the prepubertal animals. Furthermore, plasma leptin levels show no direct or predictive relation to the time of VO. The data indicate an involvement of GH in puberty onset, but do not explain the mechanism employed.
The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury
Klein, C. ; Wüstefeld, T. ; Müller, M.R. ; Trautwein, C. - \ 2005
The Journal of Clinical Investigation 115 (2005)4. - ISSN 0021-9738 - p. 860 - 869.
tumor-necrosis-factor - chronic active hepatitis - cytokine receptor gp130 - concanavalin-a - in-vivo - rat hepatocytes - transgenic mice - soluble il-6 - chemokine kc - ifn-gamma
Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6-gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A-induced (Con A-induced) model of immune-mediated hepatitis. We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect. This was demonstrated by analysis of IL-6-induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6-gp130-STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130(-/-) mice as well as in gp130-STAT1/3- and gp130-SHP2-RAS-MAPK-deficient mice. The mouse IL-8 ortholog KC (also known as Gro-alpha) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis. In summary, this study defines IL-6-gp130-STAT3-dependent gene expression in hepatocytes that mediates IL-6-triggered protection in immune-mediated Con A-induced hepatitis. Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases
Multidose streptozotocin induction of diabetes in BALB/c mice induces a dominant oxidative macrophage and a conversion of TH1 to TH2 phenotypes during disease progression
Sun, N. ; Yang, G. ; Zhao, H. ; Savelkoul, H.F.J. ; An, L. - \ 2005
Mediators of Inflammation 2005 (2005)4. - ISSN 0962-9351 - p. 202 - 209.
complete freund adjuvant - tumor-necrosis-factor - thiol redox status - pathological progression - cytokine production - transgenic mice - cells - prevention - type-1 - onset
Macrophages (Mp) are implicated in both early and late phases in type 1 diabetes development. Recent study has suggested that a balance between reductive Mp (RMp) and oxidative Mp (OMp) is possible to regulate T H1/TH2 balance. The aim of this study is to investigate the redox status of peritoneal Mp and its cytokine profile during the development of autoimmune diabetes induced by multiple low-dose streptozotocin in BALB/c mice. Meanwhile, the polarization of TH1/TH2 of splenocytes or thymocytes was also examined. We found that peritoneal Mp appeared as an "incomplete" OMp phenotype with decreased icGSH along with disease progression. The OMp showed reduced TNF-¿, IL-12, and NO production as well as defective phagocytosis activity compared to nondiabetic controls; however, there was no significant difference with IL-6 production. On the other hand, the levels of IFN-¿ or IL-4 of splenocytes in diabetic mice were significantly higher compared to the control mice. The ratio of IFN-¿ to IL-4 was also higher at the early stage of diabetes and then declined several weeks later after the occurrence of diabetes, suggesting a pathogenetic TH1 phenotype from the beginning gradually to a tendency of TH2 during the development of diabetes. Our results implied that likely OMp may be relevant in the development of type 1 diabetes; however, it is not likely the only factor regulating the TH1H/T H2 balance in MLD-STZ-induced diabetic mice.
Coffee Oil Consumption Increases Plasma Levels of 7alpha-Hydroxy-4-cholesten-3-one in Humans
Boekschoten, M.V. ; Hofman, M.K. ; Buytenhek, R. ; Schouten, E.G. ; Princen, H.M.G. ; Katan, M.B. - \ 2005
The Journal of Nutrition 135 (2005). - ISSN 0022-3166 - p. 785 - 789.
bile-acid synthesis - cholesterol-raising factor - 7-alpha-hydroxylase gene cyp7a1 - nuclear receptor lxr - liver aminotransferases - serum concentrations - transgenic mice - boiled coffee - cafestol - diterpenes
Unfiltered coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol in humans. Cafestol decreases the expression and activity of cholesterol 7-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7-hydroxylase in humans. Because liver biopsies were not feasible, we measured plasma levels of 7-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol 7-hydroxylase in the liver. Plasma 7-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing cafestol (69 mg/d) for 5 wk. Plasma levels of 7-hydroxy-4-cholesten-3-one increased by 47 ± 13% (mean ± SEM, n = 38, P = 0.001) in the first period and by 23 ± 10% (n = 31, P = 0.03) in the second treatment period. Serum cholesterol was raised by 23 ± 2% (P <0.001) in the first period and by 18 ± 2% (P <0.001) in the second period. We corrected individual 7-hydroxy-4-cholesten-3-one levels for serum cholesterol levels, because coffee oil increases serum cholesterol and 7-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the increase in 7-hydroxy-4-cholesten-3-one was 24 ± 11% (P = 0.04) in the first period and there was no effect in period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7-hydroxy-4-cholesten-3-one in humans in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in humans
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