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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    Fasting does not promote a metabolic memory effect in mouse liver
    Defour, Merel ; Hooiveld, Guido ; Weeghel, Michel van; Kersten, Sander - \ 2020
    Wageningen University
    GSE156254 - PRJNA657195 - Mus musculus
    Background: Tissues may respond differently to a particular stimulus if they have been previously exposed to that same stimulus. Here we tested the hypothesis that a strong metabolic stimulus may elicit a memory effect in the liver. To that end, we examined whether prior fasting, which profoundly impacts hepatic nutrient metabolism, may influence the metabolic response to a subsequent fast. Methods: 24 mice were exposed to two 16h fasts over a 8 week period, each time being allowed to return to their normal growth trajectory, while another group of 24 mice was fed ad libitum throughout. Of each group, half of the mice were euthanized after a 16h fast, whereas the other half was euthanized in the ab libitum fed state. Results: An acute fast significantly increased plasma NEFA, glycerol, β-hydroxybutyrate and liver triglycerides, and decreased plasma glucose, triglycerides, and liver glycogen levels. An acute fast also markedly changed the liver transcriptome, upregulating genes involved in fatty acid catabolism and downregulating genes involved in cholesterol synthesis, and majorly impacted the liver metabolome, reducing the levels of numerous amino acids, glycolysis and TCA cycle intermediates, and nucleotides. However, none of the these changes were significantly influenced by prior fasting. The limited number of genes that were significantly altered by prior fasting are likely false positives. Finally, no significant effect was observed of prior fasting on glucose tolerance. Conclusion: We conclude that previous exposure to fasting in mice does not influence the metabolic response to a subsequent fast, thus arguing against the concept of metabolic memory in the hepatic response to fasting.
    How the COVID-19 pandemic highlights the necessity of animal research
    Genzel, Lisa ; Adan, Roger ; Berns, Anton ; Beucken, Jeroen van den; Blokland, Arjan ; Boddeke, Erik H.W.G.M. ; Bogers, Willy M. ; Bontrop, Ronald ; Bulthuis, R. ; Bousema, Teun ; Clevers, Hans ; Coenen, Tineke C.J.J. ; Dam, Anne Marie van; Deen, Peter M.T. ; Dijk, K.W. van; Eggen, Bart J.L. ; Elgersma, Ype ; Erdogan, Izel ; Englitz, Bernard ; Fentener van Vlissingen, J.M. ; Fleur, Susanne la; Fouchier, Ron ; Fitzsimons, Carlos P. ; Frieling, Wilbert ; Haagmans, Bart ; Heesters, Balthasar A. ; Henckens, Marloes ; Herfst, Sander ; Hol, Elly ; Hove, Daniel van den; Jonge, Marien I. de; Jonkers, Jos ; Joosten, Leo A.B. ; Kalsbeek, Andries ; Kamermans, Maarten ; Kampinga, Harm H. ; Kas, Martien J. ; Keijer, J. ; Kersten, Sander ; Kiliaan, Amanda J. ; Kooij, Taco W.A. ; Kooijman, Sander ; Koopman, Werner J.H. ; Korosi, Aniko ; Krugers, Harm J. ; Kuiken, Thijs ; Kushner, Steven A. ; Langermans, Jan A.M. ; Lesscher, Heidi ; Lucassen, Paul J. ; Lutgens, Esther ; Netea, Mihai G. ; Noldus, Lucas P.J.J. ; Meer, Jos W.M. van der; Meye, Frank J. ; Mul, Joram D. ; Oers, Kees van; Olivier, Jocelien D.A. ; Pasterkamp, R.J. ; Philippens, Ingrid H.C.H.M. ; Prickaerts, Jos ; Pullox, Bart J.A. ; Rensen, Patrick C.N. ; Rheenen, Jacco van; Rij, Ronald P. van; Ritsma, Laila ; Rockx, Barry H.G. ; Roozendaal, Benno ; Schothorst, Evert M. van; Stittelaar, K. ; Stockhofe, Norbert ; Swaab, Dick F. ; Swart, Rik L. de; Vanderschuren, Louk J.M.J. ; Vries, Taco de; Vrij, Femke de; Wezel, Richard van; Wierenga, Corette J. ; Wiesmann, Maximilian ; Willuhn, Ingo ; Zeeuw, Chris I. de; Homberg, Judith R. - \ 2020
    Current Biology 30 (2020)18. - ISSN 0960-9822 - p. R1014 - R1018.
    Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health. In this Essay, Genzel et al. make the case for animal research in light of the COVID-19 pandemic.
    Transcriptomic signature of fasting in human adipose tissue
    Defour, Merel ; Michielsen, Charlotte C.J.R. ; O’donovan, Shauna D. ; Afman, Lydia A. ; Kersten, Sander - \ 2020
    Physiological genomics 52 (2020)10. - ISSN 1094-8341 - p. 451 - 467.
    Adipose tissue - Fasting - Human - Lipolysis - Starvation
    Little is known about gene regulation by fasting in human adipose tissue. Accordingly, the objec-tive of this study was to investigate the effects of fasting on adipose tissue gene expression in humans. To that end, subcutaneous adipose tissue biopsies were collected from 11 volunteers 2 and 26 h after consumption of a standardized meal. For comparison, epididymal adipose tissue was collected from C57Bl/6J mice in the ab libi-tum-fed state and after a 16 h fast. The timing of sampling adipose tissue roughly corresponds with the near depletion of liver glycogen. Transcriptome analysis was carried out using Affy-metrix microarrays. We found that, 1) fasting downregulated numerous metabolic pathways in human adipose tissue, including triglyceride and fatty acid synthesis, glycolysis and glycogen syn-thesis, TCA cycle, oxidative phosphorylation, mitochondrial trans-lation, and insulin signaling; 2) fasting downregulated genes involved in proteasomal degradation in human adipose tissue; 3) fasting had much less pronounced effects on the adipose tissue transcrip-tome in humans than mice; 4) although major overlap in fasting-induced gene regulation was observed between human and mouse adipose tissue, many genes were differentially regulated in the two species, including genes involved in insulin signaling (PRKAG2, PFKFB3), PPAR signaling (PPARG, ACSL1, HMGCS2, SLC22A5, ACOT1), glycogen metabolism (PCK1, PYGB), and lipid droplets (PLIN1, PNPLA2, CIDEA, CIDEC). In conclusion, although numerous genes and pathways are regulated similarly by fasting in human and mouse adipose tissue, many genes show very distinct responses to fasting in humans and mice. Our data provide a useful resource to study adipose tissue function during fasting.
    Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers
    Nascimento, Emmani B.M. ; Hangelbroek, Roland W.J. ; Hooiveld, Guido J.E.J. ; Hoeks, Joris ; Marken Lichtenbelt, Wouter D. van; Hesselink, Matthijs H.C. ; Schrauwen, Patrick ; Kersten, Sander - \ 2020
    BMC Medical Genomics 13 (2020). - ISSN 1755-8794
    Cold acclimation - Exercise training - Insulin sensitivity - Skeletal muscle - Type 2 diabetes

    Background: Cold acclimation and exercise training were previously shown to increase peripheral insulin sensitivity in human volunteers with type 2 diabetes. Although cold is a potent activator of brown adipose tissue, the increase in peripheral insulin sensitivity by cold is largely mediated by events occurring in skeletal muscle and at least partly involves GLUT4 translocation, as is also observed for exercise training. Methods: To investigate if cold acclimation and exercise training overlap in the molecular adaptive response in skeletal muscle, we performed transcriptomics analysis on vastus lateralis muscle collected from human subjects before and after 10 days of cold acclimation, as well as before and after a 12-week exercise training intervention. Results: Cold acclimation altered the expression of 756 genes (422 up, 334 down, P < 0.01), while exercise training altered the expression of 665 genes (444 up, 221 down, P < 0.01). Principal Component Analysis, Venn diagram, similarity analysis and Rank-rank Hypergeometric Overlap all indicated significant overlap between cold acclimation and exercise training in upregulated genes, but not in downregulated genes. Overlapping gene regulation was especially evident for genes and pathways associated with extracellular matrix remodeling. Interestingly, the genes most highly induced by cold acclimation were involved in contraction and in signal transduction between nerve and muscle cells, while no significant changes were observed in genes and pathways related to insulin signaling or glucose metabolism. Conclusions: Overall, our results indicate that cold acclimation and exercise training have overlapping effects on gene expression in human skeletal muscle, but strikingly these overlapping genes are designated to pathways related to tissue remodeling rather than metabolic pathways.

    Bypassing the LDL Receptor in Familial Hypercholesterolemia
    Kersten, Sander - \ 2020
    New England Journal of Medicine 383 (2020)8. - ISSN 0028-4793 - p. 775 - 776.
    Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue
    Ruppert, Philip M.M. ; Michielsen, Charlotte C.J.R. ; Hazebroek, Eric J. ; Pirayesh, Ali ; Olivecrona, Gunilla ; Afman, Lydia A. ; Kersten, Sander - \ 2020
    Molecular Metabolism 40 (2020). - ISSN 2212-8778
    Adipose tissue - Fatty acids - Insulin - Lipoprotein lipase - Triglycerides

    Objective: Studies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. Methods: Twenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. Results: Consistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. Conclusion: ANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity. This clinical trial was registered with identifier NCT03757767.

    Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA) increase triglyceride levels and decrease cholesterogenic gene expression in human HepaRG liver cells
    Louisse, Jochem ; Rijkers, Deborah ; Stoopen, Geert ; Janssen, Aafke ; Staats, Martijn ; Hoogenboom, Ron ; Kersten, Sander ; Peijnenburg, Ad - \ 2020
    Archives of Toxicology 94 (2020). - ISSN 0340-5761 - p. 3137 - 3155.
    Cholesterol - HepaRG cells - PFASs - Transcriptomics - Triglycerides

    Per- and polyfluoroalkyl substances (PFASs) are omnipresent in the environment, food chain, and humans. Epidemiological studies have shown a positive association between serum levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), and increased serum cholesterol and, in some cases, also triglyceride levels. However, causality has been questioned, as animal studies, as well as a human trial, showed a decrease in serum cholesterol and no effects or a decrease in plasma triglycerides. To obtain more insight into the effects of PFASs on these processes, the present study investigated the effects of PFOA, PFOS, and perfluorononanoic acid (PFNA) on intracellular triglyceride and cholesterol levels in human HepaRG liver cells. DNA microarray analyses were performed to provide insight into underlying mechanisms. All PFASs induced an increase in cellular triglyceride levels, but had no effect on cholesterol levels. Gene set enrichment analysis (GSEA) of the microarray data indicated that gene sets related to cholesterol biosynthesis were repressed by PFOA, PFOS, and PFNA. Other gene sets commonly affected by all PFAS were related to PERK/ATF4 signaling (induced), tRNA amino-acylation (induced), amino acid transport (induced), and glycolysis/gluconeogenesis (repressed). Moreover, numerous target genes of peroxisome proliferator-activated receptor α (PPARα) were found to be upregulated. Altogether, the present study shows that PFOA, PFOS, and PFNA increase triglyceride levels and inhibit cholesterogenic gene expression in HepaRG cells. In addition, the present study indicates that PFASs induce endoplasmic reticulum stress, which may be an important mechanism underlying some of the toxic effects of these chemicals.

    Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling
    Shrestha, Neha ; Liu, Tongyu ; Ji, Yewei ; Reinert, Rachel B. ; Torres, Mauricio ; Li, Xin ; Zhang, Maria ; Tang, Chih-Hang Anthony ; Hu, Chih-Chi Andrew ; Liu, Chengyang ; Naji, Ali ; Liu, Ming ; Lin, Jiandie D. ; Kersten, Sander ; Arvan, Peter ; Qi, Ling - \ 2020
    The Journal of Clinical Investigation 130 (2020)7. - ISSN 0021-9738 - p. 3499 - 3510.
    β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with β cell loss, but rather loss of β cell identity. Sel1L-Hrd1 ERAD controlled β cell identity via TGF-β signaling, in part by mediating the degradation of TGF-β receptor 1. Inhibition of TGF-β signaling in Sel1L-deficient β cells augmented the expression of β cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in β cells, providing a framework for therapies targeting distinct mechanisms of protein quality control
    ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling
    Shrestha, Neha ; Liu, T. ; Ji, Yewei ; Reinert, Rachel B. ; Torres, Mauricio ; Zhang, M. ; Tang, C.A. ; Hu, C.A. ; Liu, Chengyang ; Naji, Ali ; Lin, Jiandie D. ; Kersten, Sander ; Arvan, Peter ; Qi, Ling ; Hooiveld, Guido - \ 2020
    Wageningen University & Research
    Mus musculus - GSE143757 - PRJNA601502
    β cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying β cell loss in type 2 diabetes (T2D); however, the molecular drivers underlying such events remain largely unclear. Here, by performing a side-by-side comparison of mice carrying β cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy, we report that while autophagy appears necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex is required for the maintenance of β cell maturation and identity. Notably, SEL1L expression is significantly reduced in human T2D islets compared to healthy human islets. At the single cell level, we demonstrate that Sel1L deficiency is not associated with β cell loss, but rather loss of β cell identity. Mechanistically, we find that Sel1L-Hrd1 ERAD controls β cell identity via TGFβ signaling, in part by mediating the degradation of TGF-β receptor 1 (TGFβRI). Inhibition of TGFβ signaling in Sel1L-deficient β cells augments the expression of β cell maturation markers and increases the total insulin content. Our data reveal profound but distinct pathogenic effects of two major proteolytic pathways in β cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control
    MicroRNA-204-5p modulates mitochondrial biogenesis in C2C12 myotubes and associates with oxidative capacity in humans
    Houzelle, Alexandre ; Dahlmans, Dennis ; Nascimento, Emmani B.M. ; Schaart, Gert ; Jörgensen, Johanna A. ; Moonen-Kornips, Esther ; Kersten, Sander ; Wang, Xu ; Hoeks, Joris - \ 2020
    Journal of Cellular Physiology 235 (2020)12. - ISSN 0021-9541 - p. 9851 - 9863.
    C2C12 - microRNA - mitochondria - mitophagy - skeletal muscle

    Using an unbiased high-throughput microRNA (miRNA)-silencing screen combined with functional readouts for mitochondrial oxidative capacity in C2C12 myocytes, we previously identified 19 miRNAs as putative regulators of skeletal muscle mitochondrial metabolism. In the current study, we highlight miRNA-204-5p, identified from this screen, and further studied its role in the regulation of skeletal muscle mitochondrial function. Following silencing of miRNA-204-5p in C2C12 myotubes, gene and protein expression were assessed using quantitative polymerase chain reaction, microarray analysis, and western blot analysis, while morphological changes were studied by confocal microscopy. In addition, miRNA-204-5p expression was quantified in human skeletal muscle biopsies and associated with in vivo mitochondrial oxidative capacity. Transcript levels of PGC-1α (3.71-fold; p <.01), predicted as an miR-204-5p target, as well as mitochondrial DNA copy number (p <.05) and citrate synthase activity (p =.06) were increased upon miRNA-204-5p silencing in C2C12 myotubes. Silencing of miRNA-204-5p further resulted in morphological changes, induced gene expression of autophagy marker light chain 3 protein b (LC3B; q =.05), and reduced expression of the mitophagy marker FUNDC1 (q =.01). Confocal imaging revealed colocalization between the autophagosome marker LC3B and the mitochondrial marker OxPhos upon miRNA-204-5p silencing. Finally, miRNA-204-5p was differentially expressed in human subjects displaying large variation in oxidative capacity and its expression levels associated with in vivo measures of skeletal muscle mitochondrial function. In summary, silencing of miRNA-204-5p in C2C12 myotubes stimulated mitochondrial biogenesis, impacted on cellular morphology, and altered expression of markers related to autophagy and mitophagy. The association between miRNA-204-5p and in vivo mitochondrial function in human skeletal muscle further identifies miRNA-204-5p as an interesting modulator of skeletal muscle mitochondrial metabolism.

    Regulation of lipid droplet homeostasis by hypoxia inducible lipid droplet associated HILPDA
    Rosa Rodriguez, Montserrat A. de la; Kersten, Sander - \ 2020
    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1865 (2020)9. - ISSN 1388-1981
    ATGL - Fatty acids - Hypoxia - Lipid droplets - Lipolysis - Triglycerides

    Nearly all cell types have the ability to store excess energy as triglycerides in specialized organelles called lipid droplets. The formation and degradation of lipid droplets is governed by a diverse set of enzymes and lipid droplet-associated proteins. One of the lipid droplet-associated proteins is Hypoxia Inducible Lipid Droplet Associated (HILPDA). HILPDA was originally discovered in a screen to identify novel hypoxia-inducible proteins. Apart from hypoxia, levels of HILPDA are induced by fatty acids and adrenergic agonists. HILPDA is a small protein of 63 amino acids in humans and 64 amino acids in mice. Inside cells, HILPDA is located in the endoplasmic reticulum and around lipid droplets. Gain- and loss-of-function experiments have demonstrated that HILPDA promotes lipid storage in hepatocytes, macrophages and cancer cells. HILPDA increases lipid droplet accumulation at least partly by inhibiting triglyceride hydrolysis via ATGL and stimulating triglyceride synthesis via DGAT1. Overall, HILPDA is a novel regulatory signal that adjusts triglyceride storage and the intracellular availability of fatty acids to the external fatty acid supply and the capacity for oxidation.

    Mechanisms of Action of trans Fatty Acids
    Oteng, Antwi Boasiako ; Kersten, Sander - \ 2020
    Advances in Nutrition 11 (2020)3. - ISSN 2161-8313 - p. 697 - 708.
    cardiometabolic disease - cholesterogenesis - elaidic acid - ER stress - industrial trans fatty acid - inflammation - lipid metabolism - ruminant trans fatty acid

    Human studies have established a positive association between the intake of industrial trans fatty acids and the development of cardiovascular diseases, leading several countries to enact laws that restrict the presence of industrial trans fatty acids in food products. However, trans fatty acids cannot be completely eliminated from the human diet since they are also naturally present in meat and dairy products of ruminant animals. Moreover, bans on industrial trans fatty acids have not yet been instituted in all countries. The epidemiological evidence against trans fatty acids by far overshadows mechanistic insights that may explain how trans fatty acids achieve their damaging effects. This review focuses on the mechanisms that underlie the deleterious effects of trans fatty acids by juxtaposing effects of trans fatty acids against those of cis-unsaturated fatty acids and saturated fatty acids (SFAs). This review also carefully explores the argument that ruminant trans fatty acids have differential effects from industrial trans fatty acids. Overall, in vivo and in vitro studies demonstrate that industrial trans fatty acids promote inflammation and endoplasmic reticulum (ER) stress, although to a lesser degree than SFAs, whereas cis-unsaturated fatty acids are protective against ER stress and inflammation. Additionally, industrial trans fatty acids promote fat storage in the liver at the expense of adipose tissue compared with cis-unsaturated fatty acids and SFAs. In cultured hepatocytes and adipocytes, industrial trans fatty acids, but not cis-unsaturated fatty acids or SFAs, stimulate the cholesterol synthesis pathway by activating sterol regulatory element binding protein (SREBP) 2-mediated gene regulation. Interestingly, although industrial and ruminant trans fatty acids show similar effects on human plasma lipoproteins, in preclinical models, only industrial trans fatty acids promote inflammation, ER stress, and cholesterol synthesis. Overall, clearer insight into the molecular mechanisms of action of trans fatty acids may create new therapeutic windows for the treatment of diseases characterized by disrupted lipid metabolism.

    Regulation of endoplasmic reticulum-mitochondria contacts and mitochondrial dynamics by Sel1L-Hrd1 ERAD during thermogenesis
    Zhou, Zhangsen ; Torres, Mauricio ; Sha, Haibo ; Halbrook, Christopher J. ; Bergh, Françoise van den; Reinert, Rachel B. ; Yamada, Tatsuya ; Wang, Siwen ; Luo, Yingying ; Hunter, Allen H. ; Wang, Chunqing ; Sanderson, Thomas H. ; Liu, Meilian ; Taylor, Aaron ; Sesaki, Hiromi ; Lyssiotis, Costas A. ; Wu, Jun ; Kersten, Sander ; Beard, Daniel A. ; Qi, Ling - \ 2020
    Wageningen University
    GSE145895 - PRJNA608688 - Mus musculus
    Organelles such as endoplasmic reticulum (ER) and mitochondria interact with each other at specialized domains on the ER known as mitochondria-associated membranes (MAMs). Here, using three-dimensional high-resolution imaging techniques, we show that the Sel1LHrd1 protein complex, the most conserved branch of ER-associated protein degradation (ERAD), exerts a profound impact on ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover and hence the abundance of the MAM protein sigma receptor 1 (SigmaR1). Sel1L or Hrd1 deficiency in brown adipocytes impairs dynamic interaction between ER and mitochondria, leading to the formation of pleomorphic “megamitochondria” and, in some cases with penetrating ER tubule(s), in response to acute cold challenge. Mice with ERAD deficiency are cold sensitive and exhibit mitochondrial dysfunction in brown adipocytes. Mechanistically, endogenous SigmaR1 is targeted for proteasomal degradation by Sel1L-Hrd1 ERAD, whose accumulation in ERAD-deficient cells leads to mitofusin 2 (Mfn2) oligomerization, thereby linking ERAD to mitochondrial dynamics. Our study identifies Sel1L-Hrd1 ERAD as a critical determinant of ER-mitochondria contacts, thereby regulating mitochondrial dynamics and thermogenesis.
    Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes
    Zhou, Zhangsen ; Torres, Mauricio ; Sha, Haibo ; Halbrook, Christopher J. ; Bergh, Françoise van den; Reinert, Rachel B. ; Yamada, Tatsuya ; Wang, Siwen ; Luo, Yingying ; Hunter, Allen H. ; Wang, Chunqing ; Sanderson, Thomas H. ; Liu, Meilian ; Taylor, Aaron ; Sesaki, Hiromi ; Lyssiotis, Costas A. ; Wu, Jun ; Kersten, Sander ; Beard, Daniel A. ; Qi, Ling - \ 2020
    Science 368 (2020)6486. - ISSN 0036-8075 - p. 54 - 60.

    The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic “megamitochondria” with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

    A lipase fusion feasts on fat
    Ruppert, Philip M.M. ; Kersten, Sander - \ 2020
    Journal of Biological Chemistry 295 (2020)10. - ISSN 0021-9258 - p. 2913 - 2914.

    The enzyme lipoprotein lipase (LPL) is responsible for breaking down triglycerides in the blood. Mutations in LPL cause a rare but debilitating disorder characterized by excessive plasma triglyceride levels for which treatment options are limited. Nimonkar et al. now present a fusion protein between LPL and its physiological transporter GBIHBP1 that is highly active and largely resistant to physiological inhibitors of LPL. Injecting this fusion protein effectively lowers plasma triglycerides in mice and represents a promising new approach for lowering triglycerides in patients with familial chylomicronemia syndrome.

    HILPDA Uncouples Lipid Droplet Accumulation in Adipose Tissue Macrophages from Inflammation and Metabolic Dysregulation
    Dierendonck, Xanthe A.M.H. van; Rosa Rodriguez, Montserrat A. de la; Georgiadi, Anastasia ; Mattijssen, Frits ; Dijk, Wieneke ; Weeghel, Michel van; Singh, Rajat ; Borst, Jan Willem ; Stienstra, Rinke ; Kersten, Sander - \ 2020
    Cell Reports 30 (2020)6. - ISSN 2211-1247 - p. 1811 - 1822.e6.
    ATGL - fatty acid metabolism - Hilpda - inflammation - lipid droplets - macrophages - obesity

    Obesity leads to a state of chronic, low-grade inflammation that features the accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid-droplet accumulation in the development of obesity-induced adipose-tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently labeled fatty acids. Decreased lipid storage in HILPDA-deficient macrophages can be rescued by inhibition of adipose triglyceride lipase (ATGL) and is associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency does not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in macrophages. Overall, we find that HILPDA is a lipid-inducible, physiological inhibitor of ATGL-mediated lipolysis in macrophages and uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.

    Expression data from cultured mouse macrophages isolated from Hilpdaflox/flox (WT) and HilpdaΔMΦ (KO) mice treated with a mixture of fatty acids
    Dierendonck, Xanthe van; Rosa Rodriguez, Montserrat de la; Stienstra, Rinke ; Kersten, Sander - \ 2019
    Wageningen University
    GSE142295 - PRJNA596480 - Mus musculus
    Obesity leads to a state of chronic low-grade inflammation that features accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid droplet accumulation in the development of obesity-induced adipose tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently-labeled fatty acids. Decreased lipid storage in HILPDA-deficient macrophages could be rescued by inhibition of adipose triglyceride lipase (ATGL) and was associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency did not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in macrophages. Overall, we find that HILPDA is a lipid-induced physiological inhibitor of ATGL-mediated lipolysis in macrophages that uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.
    Mouse peritoneal macrophages treated with three different fatty acids
    Georgiadi, Anastasia ; Kersten, Sander - \ 2019
    Wageningen University
    GSE142294 - PRJNA596479 - Mus musculus
    Obesity leads to a state of chronic low-grade inflammation that features accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid droplet accumulation in the development of obesity-induced adipose tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently-labeled fatty acids. Decreased lipid storage in HILPDA-deficient macrophages could be rescued by inhibition of adipose triglyceride lipase (ATGL) and was associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency did not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in macrophages. Overall, we find that HILPDA is a lipid-induced physiological inhibitor of ATGL-mediated lipolysis in macrophages that uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.
    Wildtype or Hilpda KO Mouse macrophages treated with fatty acids
    Georgiadi, Anastasia ; Kersten, Sander ; Dierendonck, Xanthe van; Rosa Rodriguez, Montserrat de la; Stienstra, Rinke - \ 2019
    Wageningen University
    GSE142296 - PRJNA596477 - Mus musculus
    This SuperSeries is composed of the SubSeries listed.
    Toll-like receptors 2 and 4 control adaptive β-cell expansion in diet-induced obesity
    Ji, Yewei ; Sun, Shengyi ; Shrestha, Neha ; Darragh, Laurel B. ; Shirakawa, Jun ; Xing, Yuan ; He, Yi ; Carboneau, Bethany A. ; Kim, G. ; Kim, Hana ; An, Duo ; Ma, Minglin ; Oberholzer, Jose ; Soleimanpour, Scott A. ; Gannon, Maureen ; Liu, Chengyang ; Naji, Ali ; Kulkarni, Rohit N. ; Wang, Yong ; Kersten, Sander ; Qi, Ling - \ 2019
    Wageningen University
    GSE101392 - Mus musculus - PRJNA394076
    Adult pancreatic β cells are refractory to proliferation, a roadblock for the treatment of insulin-deficient diabetes. Consumption of energy-dense Western or high-fat diet (HFD) triggers mild adaptive β cell mass expansion to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. Here we show that Toll-like receptors (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged islet mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and CDK4 in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
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