490 results on '"van de Sluis, Bart"'
Search Results
152. COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1α via HSP90/70
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van de Sluis, Bart, primary, Groot, Arjan J., additional, Vermeulen, Jeroen, additional, van der Wall, Elsken, additional, van Diest, Paul J., additional, Wijmenga, Cisca, additional, Klomp, Leo W., additional, and Vooijs, Marc, additional
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- 2009
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153. Distinct Wilson’s Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B
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de Bie, Prim, primary, van de Sluis, Bart, additional, Burstein, Ezra, additional, van de Berghe, Peter V.E., additional, Muller, Patricia, additional, Berger, Ruud, additional, Gitlin, Jonathan D., additional, Wijmenga, Cisca, additional, and Klomp, Leo W.J., additional
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- 2007
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154. Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake
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van den Berghe, Peter V. E., primary, Folmer, Dineke E., additional, Malingré, Helga E. M., additional, van Beurden, Ellen, additional, Klomp, Adriana E. M., additional, van de Sluis, Bart, additional, Merkx, Maarten, additional, Berger, Ruud, additional, and Klomp, Leo W. J., additional
- Published
- 2007
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155. COMMD1: A Novel Protein Involved in the Proteolysis of Proteins
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van de Sluis, Bart, primary, Groot, Arjan J., additional, Wijmenga, Cisca, additional, Vooijs, Marc, additional, and Klomp, Leo W., additional
- Published
- 2007
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156. Increased Activity of Hypoxia-Inducible Factor 1 Is Associated with Early Embryonic Lethality in Commd1 Null Mice
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van de Sluis, Bart, primary, Muller, Patricia, additional, Duran, Karen, additional, Chen, Amy, additional, Groot, Arjan J., additional, Klomp, Leo W., additional, Liu, Paul P., additional, and Wijmenga, Cisca, additional
- Published
- 2007
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157. Characterization of COMMD protein–protein interactions in NF-κB signalling
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de Bie, Prim, primary, van de Sluis, Bart, additional, Burstein, Ezra, additional, Duran, Karen J., additional, Berger, Ruud, additional, Duckett, Colin S., additional, Wijmenga, Cisca, additional, and Klomp, Leo W. J., additional
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- 2006
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158. Transgene Design.
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van de Sluis, Bart and Voncken, Jan Willem
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- 2011
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159. A novel role for XIAP in copper homeostasis through regulation of MURR1
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Burstein, Ezra, primary, Ganesh, Lakshmanan, additional, Dick, Robert D, additional, van De Sluis, Bart, additional, Wilkinson, John C, additional, Klomp, Leo W J, additional, Wijmenga, Cisca, additional, Brewer, George J, additional, Nabel, Gary J, additional, and Duckett, Colin S, additional
- Published
- 2003
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160. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan.
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Baker, Darren J., Dawlaty, Meelad M., Wijshake, Tobias, Jeganathan, Karthik B., Malureanu, Liviu, van Ree, Janine H., Crespo-Diaz, Ruben, Reyes, Santiago, Seaburg, Lauren, Shapiro, Virginia, Behfar, Atta, Terzic, Andre, van de Sluis, Bart, and van Deursen, Jan M.
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ANEUPLOIDY ,CARCINOGENESIS ,MITOSIS ,REACTIVE oxygen species ,ANIMAL models in research ,MICE ,PREVENTION - Abstract
The BubR1 gene encodes for a mitotic regulator that ensures accurate segregation of chromosomes through its role in the mitotic checkpoint and the establishment of proper microtubule-kinetochore attachments. Germline mutations that reduce BubR1 abundance cause aneuploidy, shorten lifespan and induce premature ageing phenotypes and cancer in both humans and mice. A reduced BubR1 expression level is also a feature of chronological ageing, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high-level expression of BubR1 preserves genomic integrity and reduces tumorigenesis, even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras. We find that BubR1 overabundance exerts its protective effect by correcting mitotic checkpoint impairment and microtubule-kinetochore attachment defects. Furthermore, sustained high-level expression of BubR1 extends lifespan and delays age-related deterioration and aneuploidy in several tissues. Collectively, these data uncover a generalized function for BubR1 in counteracting defects that cause whole-chromosome instability and suggest that modulating BubR1 provides a unique opportunity to extend healthy lifespan. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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161. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
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Baker, Darren J., Wijshake, Tobias, Tchkonia, Tamar, LeBrasseur, Nathan K., Childs, Bennett G., van de Sluis, Bart, Kirkland, James L., and van Deursen, Jan M.
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AGING ,FLUORESCENCE microscopy ,ADIPOSE tissues ,PHENOTYPES ,BIOMARKERS ,LABORATORY mice - Abstract
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16
Ink4a , to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a -positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a -positive senescent cells upon drug treatment. In tissues-such as adipose tissue, skeletal muscle and eye-in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a -expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. [ABSTRACT FROM AUTHOR]- Published
- 2011
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162. COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1α via HSP90/70.
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van de Sluis, Bart, Groot, Arjan J., Vermeulen, Jeroen, van der Wall, Elsken, Diest, Paul J. van, Wijmenga, Cisca, Klomp, Leo W., and Vooijs, Marc
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PROTEOLYSIS , *PROTEIN metabolism , *HOMEOSTASIS , *PHYSIOLOGICAL control systems , *COPPER metabolism , *COPPER in the body , *SODIUM channels , *UBIQUITIN , *TUMOR suppressor genes - Abstract
Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-κB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1α protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90β for binding to the NH2-terminal DNAbinding and heterodimerization domain of HIF-1α to regulate HIF-1α stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90β/HSP70 in the ubiquitin and O2-independent regulation of HIF-1α. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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163. Nuclear-Cytosolic Transport of COMMD1 Regulates NF-κB and HIF-1 Activity.
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Muller, Patricia A. J., van de Sluis, Bart, Groot, Arjan J., Verbeek, Dineke, Vonk, Willianne I. M., Maine, Gabriel N., Burstein, Ezra, Wijmenga, Cisca, Vooijs, Marc, Reits, Eric, and Klomp, Leo W. J.
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COPPER metabolism , *TRANSCRIPTION factors , *NF-kappa B , *HYPOXEMIA , *PROTEINS , *CELLS - Abstract
Copper metabolism MURR1 domain1 (COMMD1) is a novel inhibitor of the transcription factors NF-κB and HIF-1, which play important roles in inflammation and tumor growth, respectively. In this study, we identified two highly conserved nuclear export signals (NESs) in COMMD1 and revealed that these NESs were essential and sufficient to induce maximal nuclear export of COMMD1. Inhibition of CRM1-mediated nuclear export by Leptomycin B resulted in nuclear accumulation of COMMD1. In addition, low oxygen concentrations induced the active export of COMMD1 from the nucleus in a CRM1-dependent manner. Disruption of the NESs in COMMD1 increased the repression of COMMD1 in transcriptional activity of NF-κB and HIF-1. In conclusion, these data indicate that COMMD1 undergoes constitutive nucleocytoplasmic transport as a novel mechanism to regulate NF-κB and HIF-1 signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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164. The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis.
- Author
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Heida, Andries, Gruben, Nanda, Catrysse, Leen, Koehorst, Martijn, Koster, Mirjam, Kloosterhuis, Niels J., Gerding, Albert, Havinga, Rick, Bloks, Vincent W., Bongiovanni, Laura, Wolters, Justina C., van Dijk, Theo, van Loo, Geert, de Bruin, Alain, Kuipers, Folkert, Koonen, Debby P.Y., and van de Sluis, Bart
- Abstract
Obesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development. A murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20
LKO ). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1–13 C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways. Hepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20LKO mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20LKO mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20LKO mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20LKO mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice. The hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients. • The hepatocytic IKK:NF-κB axis is a metabolic regulator. • Hepatocyte IKK-mediated NF-κB activation drives liver steatosis but not liver inflammation. • Chronic activation of the hepatocyte NF-κB signaling pathway promotes de novo lipogenesis and cholesterol synthesis. • IKK-mediated NF-κB activation in hepatocytes contributes to MAFLD severity. [ABSTRACT FROM AUTHOR]- Published
- 2021
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165. COMMD1.
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Van de Sluis, Bart, Groot, Arjan J., Wijmenga, Cisca, Vooijs, Marc, and Klomp, Leo W.
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- 2007
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166. Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD).
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Vos, Dyonne Y. and van de Sluis, Bart
- Abstract
Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease, has become the leading cause of chronic liver disease worldwide. In addition to hepatic accumulation of triglycerides, dysregulated cholesterol metabolism is an important contributor to the pathogenesis of MAFLD. Maintenance of cholesterol homeostasis is highly dependent on cellular cholesterol uptake and, subsequently, cholesterol transport to other membrane compartments, such as the endoplasmic reticulum (ER). The endolysosomal network is key for regulating cellular homeostasis and adaptation, and emerging evidence has shown that the endolysosomal network is crucial to maintain metabolic homeostasis. In this review, we will summarize our current understanding of the role of the endolysosomal network in cholesterol homeostasis and its implications in MAFLD pathogenesis. Although multiple endolysosomal proteins have been identified in the regulation of cholesterol uptake, intracellular transport, and degradation, their physiological role is incompletely understood. Further research should elucidate their role in controlling metabolic homeostasis and development of fatty liver disease. • The intracellular cholesterol transport is tightly regulated by the endocytic and lysosomal network. • Dysfunction of the endolysosomal network affects hepatic lipid homeostasis. • The endosomal sorting of lipoprotein receptors is precisely regulated and is not a bulk process. [ABSTRACT FROM AUTHOR]
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- 2021
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167. Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16.
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van de Sluis, Bart J. A., Breen, Matthew, Nanji, Manoj, van Wolferen, Monique, de Jong, Pieter, Binns, Matthew M., Pearson, Peter L., Kuipers, Jeroen, Rothuizen, Jan, Cox, Diane W., Wijmenga, Cisca, and van Oost, Bernard A.
- Abstract
Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog. The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD). Mutations in the ATP7B genes have also been demonstrated in mouse and rat. The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity. By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease. We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence hybridization (FISH). C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, demonstrating that WD cannot be homologous to CT. The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22.2-22.5. A transcribed sequence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes. [ABSTRACT FROM AUTHOR]
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- 1999
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168. Editorial introductions.
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Westerterp, Marit and van de Sluis, Bart
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- 2018
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169. Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH
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van der Pol, Atze, Gil, Andres, Silljé, Herman H. W., Tromp, Jasper, Ovchinnikova, Ekaterina S., Vreeswijk-Baudoin, Inge, Hoes, Martijn, Domian, Ibrahim J., van de Sluis, Bart, van Deursen, Jan M., Voors, Adriaan A., van Veldhuisen, Dirk J., van Gilst, Wiek H., Berezikov, Eugene, van der Harst, Pim, de Boer, Rudolf A., Bischoff, Rainer, and van der Meer, Peter
- Abstract
OPLAH is cardioprotective for myocardial infarction, and its substrate 5-oxoproline is a putative circulating marker for heart failure.
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- 2017
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170. Selective Hepatic Cbs Knockout Aggravates Liver Damage, Endothelial Dysfunction and ROS Stress in Mice Fed a Western Diet.
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Lambooy, Sebastiaan, Heida, Andries, Joschko, Christian, Nakladal, Dalibor, van Buiten, Azuwerus, Kloosterhuis, Niels, Huijkman, Nicolette, Gerding, Albert, van de Sluis, Bart, Henning, Robert, and Deelman, Leo
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WESTERN diet , *ENDOTHELIUM diseases , *NON-alcoholic fatty liver disease , *FATTY acid oxidation , *ANIMAL feeds , *LIVER - Abstract
Cystathionine-β-synthase (CBS) is highly expressed in the liver, and deficiencies in Cbs lead to hyperhomocysteinemia (HHCy) and disturbed production of antioxidants such as hydrogen sulfide. We therefore hypothesized that liver-specific Cbs deficient (LiCKO) mice would be particularly susceptible to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced by a high-fat high-cholesterol (HFC) diet; LiCKO and controls were split into eight groups based on genotype (con, LiCKO), diet (normal diet, HFC), and diet duration (12 weeks, 20 weeks). LiCKO mice displayed intermediate to severe HHCy. Plasma H2O2 was increased by HFC, and further aggravated in LiCKO. LiCKO mice fed an HFC diet had heavier livers, increased lipid peroxidation, elevated ALAT, aggravated hepatic steatosis, and inflammation. LiCKO mice showed decreased L-carnitine in the liver, but this did not result in impaired fatty acid oxidation. Moreover, HFC-fed LiCKO mice demonstrated vascular and renal endothelial dysfunction. Liver and endothelial damage correlated significantly with systemic ROS status. In conclusion, this study demonstrates an important role for CBS in the liver in the development of NAFLD, which is most probably mediated through impaired defense against oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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171. THU-224 CRISPR/Cas9-mediated somatic gene editing in adult mice reveals hepatic KLB as a regulator of bile acid synthesis and hepatic lipid metabolism.
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Aaldijk, Alexandra, Struik, Dicky, Verzijl, Cristy, Havinga, Rick, Hovingh, Milaine, Huijkman, Nicolette, Smit, Marieke, van de Sluis, Bart, and Jonker, Johan
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- 2024
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172. Hepatic Retromer is critical for systemic cholesterol homeostasis via shaping the endo-lysosomal organization.
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Vos, Dyonne, Barbosa, Markus, Heida, Andries, Smit, Marieke, Huijkmann, Nicolette, Kloosterhuis, Niels, Havinga, Rick, De Boer, Jan Freark, Kuivenhoven, Jan Albert, and Van De Sluis, Bart
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HOMEOSTASIS , *CHOLESTEROL , *ORGANIZATION - Published
- 2024
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173. FRI-549-YI Hepatic loss of the endosomal sorting complex Retromer delays postnatal liver maturation and increases hepatocellular proliferation.
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Barbosa, Markus Gregorio, Vos, Dyonne, Heida, Andries, Koster, Mirjam, Bloks, Vincent, Kloosterhuis, Niels, Smit, Marieke, Bongiovanni, Laura, Struik, Dicky, Jonker, Johan, Kuivenhoven, Jan Albert, and van de Sluis, Bart
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- 2024
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174. Mice with a deficiency in Peroxisomal Membrane Protein 4 (PXMP4) display mild changes in hepatic lipid metabolism.
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Blankestijn, Maaike, Bloks, Vincent W., Struik, Dicky, Huijkman, Nicolette, Kloosterhuis, Niels, Wolters, Justina C., Wanders, Ronald J. A., Vaz, Frédéric M., Islinger, Markus, Kuipers, Folkert, van de Sluis, Bart, Groen, Albert K., Verkade, Henkjan J., and Jonker, Johan W.
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MEMBRANE proteins , *LIPID metabolism , *ETHER lipids , *ENTEROHEPATIC circulation , *UNSATURATED fatty acids , *PLASMA products , *BILE acids , *MICE - Abstract
Peroxisomes play an important role in the metabolism of a variety of biomolecules, including lipids and bile acids. Peroxisomal Membrane Protein 4 (PXMP4) is a ubiquitously expressed peroxisomal membrane protein that is transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα), but its function is still unknown. To investigate the physiological function of PXMP4, we generated a Pxmp4 knockout (Pxmp4−/−) mouse model using CRISPR/Cas9-mediated gene editing. Peroxisome function was studied under standard chow-fed conditions and after stimulation of peroxisomal activity using the PPARα ligand fenofibrate or by using phytol, a metabolite of chlorophyll that undergoes peroxisomal oxidation. Pxmp4−/− mice were viable, fertile, and displayed no changes in peroxisome numbers or morphology under standard conditions. Also, no differences were observed in the plasma levels of products from major peroxisomal pathways, including very long-chain fatty acids (VLCFAs), bile acids (BAs), and BA intermediates di- and trihydroxycholestanoic acid. Although elevated levels of the phytol metabolites phytanic and pristanic acid in Pxmp4−/− mice pointed towards an impairment in peroxisomal α-oxidation capacity, treatment of Pxmp4−/− mice with a phytol-enriched diet did not further increase phytanic/pristanic acid levels. Finally, lipidomic analysis revealed that loss of Pxmp4 decreased hepatic levels of the alkyldiacylglycerol class of neutral ether lipids, particularly those containing polyunsaturated fatty acids. Together, our data show that while PXMP4 is not critical for overall peroxisome function under the conditions tested, it may have a role in the metabolism of (ether)lipids. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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175. Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice.
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Heida, Andries, van Dijk, Theo, Smit, Marieke, Koehorst, Martijn, Koster, Mirjam, Kloosterhuis, Niels, Havinga, Rick, Bloks, Vincent W., Wolters, Justina C., de Bruin, Alain, Kuivenhoven, Jan Albert, de Boer, Jan Freark, Kuipers, Folkert, and van de Sluis, Bart
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BILE acids , *WISKOTT-Aldrich syndrome , *HIGH cholesterol diet , *CHOLESTEROL , *INTESTINAL absorption , *MICE - Abstract
The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes. Male and female intestine-specific WASHC1-deficient mice (Washc1 IKO) were challenged with either a standard chow diet or a high-cholesterol (1.25 %) diet (HCD). Washc1 IKO mice fed a standard diet did not present any apparent phenotype, but when fed an HCD, their hepatic cholesterol levels were ~ 50 % lower compared to those observed in control mice. The intestinal cholesterol absorption was almost 2-fold decreased in Washc1 IKO mice, which translated into increased fecal neutral sterol loss. The intestinal expression of cholesterogenic genes, such as Hmgcs1 , Hmgcr , and Ldlr , was significantly higher in Washc1 IKO mice than in control mice and correlated with increased whole-body de novo cholesterol synthesis, likely to compensate for impaired intestinal cholesterol absorption. Unexpectedly, the ratio of biliary 12α−/non-12α-hydroxylated bile acids (BAs) was decreased in Washc1 IKO mice and reversing this reduced ratio by feeding the mice with the HCD supplemented with 0.5 % (w /w) sodium cholate normalized the improvement of hepatic cholesterol levels in Washc1 IKO mice. Our data indicate that the intestinal WASH complex plays an important role in intestinal cholesterol absorption, likely by modulating biliary BA composition. [Display omitted] • The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is essential for intestinal cholesterol absorption. • Intestinal loss of the WASH complex reduces the ratio of biliary 12α/non-12α-hydroxylated bile acids (BAs). • The reduced intestinal cholesterol absorption in Washc1 IKO mice is mainly caused by changes in the composition of BAs • Increasing 12α/non-12α-hydroxylated BA ratio normalizes the reduced hepatic cholesterol levels in Washc1 IKO mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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176. Exploring the role of novel candidates in the initiation and progression of non-alcoholic fatty liver disease
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Heida, Andries Hendrik, van de Sluis, Bart, and de Bruin, Alain
- Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD includes multiple liver injuries, including accumulation of fats (lipids), known as steatosis, liver cell damage combined with liver inflammation (non-alcoholic steatohepatitis (NASH)), and the formation (fibrosis) of scar tissue (also known as cirrhosis). While steatosis and inflammation of the liver are reversible, NASH can also progress to irreversible disease states, such as cirrhosis and liver cancer. NAFLD also increases the risk of atherosclerotic cardiovascular disease (ASCVD) and NAFLD is strongly associated with obesity, insulin resistance, and diabetes. Currently, there are no drugs to treat NAFLD. To treat NAFLD in the future, more knowledge is required about how NAFLD arises and how it develops into NASH and liver cancer. The work in my thesis shows the importance of chronic liver inflammation in the initiation of NAFLD and increasing the risk of ASCVD. We showed that chronic liver inflammation promotes the production of different types of lipids in the liver. We also uncovered that a ‘long non-coding RNA’ (lncRNA), recently associated with the NASH grade, does not play a direct role in the development of NAFLD. However, we found that this lncRNA may contribute to the development of liver cancer in a preclinic mouse model of NAFLD and liver cancer. Finally, we provided more molecular insight into the processes that facilitate absorption of cholesterol in the gut. This knowledge can be used to better understand the wide variation in intestinal absorption of cholesterol in humans.
- Published
- 2023
177. Functional Insights Into Novel Regulators of Plasma Lipids: STAP1 and GPR146
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Loaiza, Natalia, Kuivenhoven, Jan Albert, and van de Sluis, Bart
- Abstract
Elucidating the mechanisms how novel genes regulate plasma lipids promises to expand the current understanding of the origins of dyslipidemias and atherosclerotic cardiovascular diseases (ASCVD). New insights can also offer possibilities to develop additional treatment strategies to alleviate ASCVD, currently the largest cause of death worldwide. This thesis offers insights into how STAP1 (Signal Transducing Adaptor Family Member 1) and GPR146 (G-protein coupled receptor 146) regulate plasma lipids. Our functional studies into STAP1, a previously proposed Familial Hypercholesterolemia (FH) gene, show that STAP1 does not regulate LDL-cholesterol in mice or humans. Consequently, we have proposed to delist STAP1 as an FH gene. For GPR146, we studied common and rare variants and their associated plasma lipid profiles in large population cohorts. Our findings support a novel role for GPR146 in human hypolipidemia, with carriers of GPR146 loss-of-function variants exhibiting an overall beneficial cardiometabolic risk profile. It remains to be demonstrated whether genetic or pharmaceutical inhibition of GPR146 confers atheroprotection in humans. We also found that GPR146 expression is negatively associated with SR-B1 protein levels. However, our experimental findings indicated that SR-B1 probably is not the causal driver of this phenotype. In conclusion, our studies suggest that hepatic GPR146 inactivation might constitute a potential therapeutic strategy to reduce plasma cholesterol and atherosclerosis independently of the LDLR and SR-B1. However, the current biological understanding of GPR146 functions and interactions, hepatic and extrahepatic, remains incomplete; therefore, additional efforts to clarify its true potential as a drug target are required.
- Published
- 2023
178. Understanding hepatic Glycogen Storage Disease type Ia: role of phenotypic heterogeneity and nutrient sensors
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Martijn Rutten, van de Sluis, Bart, and Oosterveer, Maaike
- Abstract
Patients with Glycogen Storage Disease type Ia (GSD Ia), a rare inherited disease affecting glucose metabolism, are at increased risk for liver tumour development but harbour interindividual differences in disease presentation and progression. The studies in this thesis focus on modelling clinical heterogeneity in GSD Ia in mice, and understanding the mechanisms underlying liver tumour development in GSD Ia. As both aspects are currently unresolved, they pose major challenges to optimal healthcare for GSD Ia patients. We show that somatic CRISPR/Cas9-mediated editing of hepatic glucose-6-phosphatase (G6pc, the gene affected in GSD Ia) allows to generate a spectrum of GSD Ia phenotypes and to simultaneously edit multiple hepatic genes. This approach may hence be employed to investigate the contribution of individual differences between patients, such as variations in residual G6PC1 activity and the interaction between G6PC1 other genes, to liver tumour development in GSD Ia. In addition, our work shows that activation of the nutrient sensor Carbohydrate Response Element Binding Protein (ChREBP) protects against advanced liver disease and decelerates liver tumour development in GSD Ia. Insights from this work help to better understand mechanisms underlying tumorigenesis in GSD Ia, and highlight the importance of establishing the content-specific roles of ChREBP to define its therapeutic potential. Finally, our work on the nutrient sensor Sirtuin 1 (SIRT1) reveals previously unknown adaptations in NAD+ and methyl (one-carbon) metabolism in hepatic GSD Ia, which may provide novel directions for (pre)clinical research on and therapy development for GSD Ia.
- Published
- 2022
179. The chemotherapeutic drug doxorubicin does not exacerbate p16Ink4a-positive senescent cell accumulation and cardiometabolic disease development in young adult female LDLR-deficient mice.
- Author
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Postmus, Andrea C., Kruit, Janine K., Eilers, Roos E., Havinga, Rick, Koster, Mirjam H., Johmura, Yoshikazu, Nakanishi, Makoto, van de Sluis, Bart, and Jonker, Johan W.
- Subjects
- *
DOXORUBICIN , *WEIGHT loss , *YOUNG adults , *HEART metabolism disorders , *WHITE adipose tissue , *ADULT development - Abstract
Cancer survivors who received chemotherapy, such as the anthracycline doxorubicin (DOX), have an increased risk of developing complications later in life, including the development of chronic metabolic diseases. Although the etiology of this increased risk for late metabolic complications in cancer survivors is poorly understood, a causal role of therapy-induced senescent cells has been suggested. To study the role of cellular senescence in chemotherapy-induced metabolic complications, young adult female low-density lipoprotein receptor-deficient (Ldlr −/− )-p16-3MR mice, in which p16Ink4a-positive (p16Ink4a+) senescent cells can be genetically eliminated, were treated with four weekly injections of DOX (2.5 mg/kg) followed by a high-fat high-cholesterol diet for 12 weeks. While DOX treatment induced known short-term effects, such as reduction in body weight, gonadal fat mass, and adipose tissue inflammation, it was not associated with significant long-term effects on glucose homeostasis, hepatic steatosis, or atherosclerosis. We further found no evidence of DOX-induced accumulation of p16Ink4a+-senescent cells at 1 or 12 weeks after DOX treatment. Neither did we observe an effect of elimination of p16Ink4a+-senescent cells on the development of diet-induced cardiometabolic complications in DOX-treated mice. Other markers for senescence were generally also not affected except for an increase in p21 and Cxcl10 in gonadal white adipose tissue long-term after DOX treatment. Together, our study does not support a significant role for p16Ink4a+-senescent cells in the development of diet-induced cardiometabolic disease in young adult DOX-treated female Ldlr −/− mice. These findings illustrate the need of further studies to understand the link between cancer therapy and cardiometabolic disease development in cancer survivors. • Doxorubicin treatment induces acute gonadal white adipose tissue inflammation. • DOX does not induce p16Ink4a+-senescent cells in young adult female Ldlr −/− -p16-3MR mice. • DOX treatment results in a long-term reduction in gonadal white adipose tissue mass. • Long-term cardiometabolic health in young adult female HFC-diet-fed mice is not affected by DOX. • Clearance of p16Ink4a+-senescent cells does not improve diet-induced atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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180. Crosstalk between lipoproteins and leukocytes
- Author
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Venetia Bazioti, van de Sluis, Bart, and Westerterp, Marit
- Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide and atherosclerosis is the primary underlying cause. Main risk factors for atherosclerosis are elevated plasma low-density lipoprotein-cholesterol (LDL-c) levels and inflammation. Leukocytosis, the expansion of white blood cells, positively associates with CVD in humans, independent of inflammation. Studies in animal models have demonstrated that high-density lipoprotein-cholesterol (HDL-c) suppresses leukocytosis. We found a negative association between HDL-c and blood leukocytes in the LifeLines DEEP cohort, as such providing translational evidence for the findings in animal models. Leukocytosis in humans with myeloproliferative diseases is accompanied by low plasma LDL-c levels. Regardless, these patients are at increased risk of CVD. We propose that this is due to leukocytosis, and that stem cells take up high amounts of LDL-c to induce their proliferation leading to leukocytosis, which decreases plasma LDL-c. We also focused on a specific leukocyte subset, T cells. During atherogenesis and aging, T cells accumulate cholesterol leading to differentiation into distinct subsets with either pro- or anti-inflammatory characteristics. To investigate the effect of T cell cholesterol accumulation on T cell aging and atherosclerosis, we generated a mouse model with combined deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/ABCG1) specifically in T cells. T cell Abca1/Abcg1 deficiency increased T cell apoptosis and senescence, and decreased atherosclerosis in middle-aged mice. Our findings suggest that T cell cholesterol efflux pathways are crucial in maintaining peripheral T cell numbers and T cell tolerance, especially during aging.
- Published
- 2022
181. PCSK9 and syndecan-1 in renal disease-related dyslipidemia
- Author
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Shrestha, Pragyi, van den Born, Jaap, and van de Sluis, Bart
- Subjects
carbohydrates (lipids) ,lipids (amino acids, peptides, and proteins) - Abstract
Liver is the primary organ for clearance of triglyceride-rich remnant lipoproteins (TRL) via LDL receptor (LDLR), ), LDLR-related protein-1 (LRP1) and syndecan-1. Elevated plasma TRL due to reduced liver clearance is a major cause of dyslipidemia, cardiovascular disease and mortality in chronic kidney disease (CKD). Although substantial effort has been put into understanding the molecular mechanisms underlying dyslipidemia in CKD and development of novel therapies, dyslipidemia related to CKD still remains a huge challenge. Recently, heparan sulfate proteoglycans (HSPG) has been reported to facilitate LDLR degradation by proprotein convertase subtilisin kexin type-9 (PCSK9). In this thesis, we have investigated i) the effects of CKD on primary hepatic lipoprotein receptors (LDLR, LRP1 and syndecan-1); ii) the interaction of PCSK9 and hepatic HSPGs in connection to plasma lipids and iii) whether lipid lowering therapies are associated with reductions in plasma PCSK9 and syndecan-1 and clinical outcomes. The studies reported in this thesis provide novel insights into the mechanisms underlying dyslipidemia in renal diseases that involve increased hepatic HSPG interaction with PCSK9 leading to reduced clearance of TRL. At present, where current cholesterol-lowering strategies to treat dyslipidemia in CKD are still insufficient, studies present in this thesis suggest that PCSK9 inhibition can be beneficial in improving lipid levels in CKD. Further, our study opens new venues for future development of cost-effective heparin mimetics as PCSK9 inhibitors.
- Published
- 2022
182. Mirabegron-induced brown fat activation does not exacerbate atherosclerosis in mice with a functional hepatic ApoE-LDLR pathway.
- Author
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Ying, Zhixiong, van Eenige, Robin, Beerepoot, Rosa, Boon, Mariëtte R., Kloosterhuis, Niels J., van de Sluis, Bart, Bartelt, Alexander, Rensen, Patrick C.N., and Kooijman, Sander
- Subjects
- *
BROWN adipose tissue , *WHITE adipose tissue , *ATHEROSCLEROSIS , *ADIPOSE tissues , *LIPOPROTEIN receptors , *APOLIPOPROTEIN E , *CHYLOMICRONS - Abstract
Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2023
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183. Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling.
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Haiying Li, Yeon Koo, Xicheng Mao, Sifuentes-Dominguez, Luis, Morris, Lindsey L., Da Jia, Naoteru Miyata, Faulkner, Rebecca A., van Deursen, Jan M., Vooijs, Marc, Billadeau, Daniel D., van de Sluis, Bart, Cleaver, Ondine, and Burstein, Ezra
- Subjects
- *
ENDOSOMES , *CELL membranes , *TRANSCRIPTION factors , *PROTEIN binding ,COPPER metabolism genetics - Abstract
Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD-CCDC22-CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
184. Sorting out cholesterol metabolism: novel insights into the mechanism of endosomal trafficking of lipoprotein receptors
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Melinde Wijers, van de Sluis, Bart, and Kuivenhoven, Jan Albert
- Subjects
Retromer ,Genome editing ,Chemistry ,Endosome ,Cas9 ,LDL receptor ,CRISPR ,Lipid metabolism ,LRP1 ,Cell biology - Abstract
This thesis highlights a crucial role for the CCC and WASH complexes in hepatic cholesterol uptake by orchestrating the endosomal recycling of LDLR, LRP1 and SR-BI. We provided novel insights into how the different CCC components interrelate to maintain the integrity of the CCC complex. We introduced somatic CRISPR/Cas9 gene editing technology, a sophisticated methodology to study the interplay between different endosomal sorting complexes in vivo. Using this technology, we found that both retriever and retromer likely participate in the CCC-WASH axis to facilitate endosomal recycling of LDLR, but not SR-BI. Moreover, we showed that hepatic retromer controls plasma TG levels independently of the CCC-WASH pathway. Overall, this thesis provides novel insights into the intricate interplay between the different protein complexes of endosomal sorting machineries in the regulation of lipid metabolism.
- Published
- 2019
185. IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner
- Author
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Maleszewska, Monika, Moonen, Jan-Renier A.J., Huijkman, Nicolette, van de Sluis, Bart, Krenning, Guido, and Harmsen, Martin C.
- Subjects
- *
INTERLEUKIN-1 , *TRANSFORMING growth factors-beta , *DRUG synergism , *ENDOTHELIAL cells , *MESENCHYMAL stem cells , *NF-kappa B - Abstract
Abstract: Endothelial to mesenchymal transition (EndMT) contributes to fibrotic diseases. The main inducer of EndMT is TGFβ signaling. TGFβ2 is the dominant isoform in the physiological embryonic EndMT, but its role in the pathological EndMT in the context of inflammatory co-stimulation is not known. The aim of this study was to investigate TGFβ2-induced EndMT in the context of inflammatory IL-1β signaling. Co-stimulation with IL-1β and TGFβ2, but not TGFβ1, caused synergistic induction of EndMT. Also, TGFβ2 was the only TGFβ isoform that was progressively upregulated during EndMT. External IL-1β stimulation was dispensable once EndMT was induced. The inflammatory transcription factor NFκB was upregulated in an additive manner by IL-1β and TGFβ2 co-stimulation. Co-stimulation also led to the nuclear translocation of NFκB which was sustained over long-term treatment. Activation of NFκB was indispensable for the co-induction of EndMT. Our data suggest that the microenvironment at the verge between inflammation (IL-1β) and tissue remodeling (TGFβ2) can strongly promote the process of EndMT. Therefore our findings provide new insights into the mechanisms of pathological EndMT. [Copyright &y& Elsevier]
- Published
- 2013
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- View/download PDF
186. The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance
- Author
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Marieke Smit, Dyonne Y. Vos, Michelle Y. Jäckstein, Judith Klumperman, Folkert Kuipers, Daphne Dekker, Daniel D. Billadeau, Niels J. Kloosterhuis, Arnold von Eckardstein, Melinde Wijers, Nicolette C. A. Huijkman, Sanne Wilbrink, Bart van de Sluis, Paolo Zanoni, Jan Albert Kuivenhoven, Justina C. Wolters, Ydwine T. van der Veen, Nalan Liv, Theo H. van Dijk, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), University of Zurich, and van de Sluis, Bart
- Subjects
0301 basic medicine ,Apolipoprotein E ,Male ,medicine.medical_specialty ,Vesicular Transport Proteins ,610 Medicine & health ,Mice, Transgenic ,2700 General Medicine ,APOLIPOPROTEIN-E ,DEFICIENT MICE ,WASH complex ,03 medical and health sciences ,chemistry.chemical_compound ,ESTER TRANSFER PROTEIN ,Mice ,0302 clinical medicine ,High-density lipoprotein ,Internal medicine ,540 Chemistry ,medicine ,Animals ,Scavenger receptor ,10038 Institute of Clinical Chemistry ,Medicine(all) ,Chemistry ,Cholesterol ,Cholesterol, HDL ,Microfilament Proteins ,SR-BI ,General Medicine ,Cholesterol, LDL ,DEGRADATION ,Scavenger Receptors, Class B ,LRP1 ,A-I ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,TISSUE UPTAKE ,Liver ,030220 oncology & carcinogenesis ,LDL receptor ,Kexin ,SELECTIVE UPTAKE ,lipids (amino acids, peptides, and proteins) ,Female ,HIGH-DENSITY-LIPOPROTEIN ,SCAVENGER RECEPTOR BI ,Research Article - Abstract
The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1. Hepatic WASH ablation also reduced the surface levels of scavenger receptor class B type I and, concomitantly, selective uptake of HDL cholesterol into the liver. Furthermore, we found that WASHC1 deficiency increases LDLR proteolysis by the inducible degrader of LDLR, but does not affect proprotein convertase subtilisin/kexin type 9-mediated LDLR degradation. Remarkably, however, loss of hepatic WASHC1 may sensitize LRP1 for proprotein convertase subtilisin/kexin type 9-induced degradation. Altogether, these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes.
- Published
- 2019
187. The gut microbiota in cardiovascular disease: Interactions between the diet, microbiota and the gut immune barrier
- Author
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Brandsma, Eelke Thijs, van de Sluis, Bart, and Koonen, Debby
- Subjects
digestive system - Abstract
Cardiovascular disease (CVD) causes 17.7 million deaths annually worldwide and is therefore a major health burden to our society. Over the last century, CVD treatment has greatly improved. The discovery of cholesterol lowering drugs has led to a strongly improved treatment of CVD. However, atherosclerosis, the main underlying cause of CVD, is not solely a cholesterol-driven disease. Recently a large human study showed that inflammation is also an important factor in the development of atherosclerosis. Understanding the factors that contribute to inflammation is therefore of great importance. The gut microbiota is one such factor that has recently been linked to cardiovascular disease and inflammation. However, it is unknown whether alterations in microbiota composition can contribute to CVD development and if interactions between the gut immune barrier, diet and gut microbiota can affect systemic inflammation and atherosclerosis. In this thesis, we used mouse models to understand how the interaction between the diet, gut microbiota and intestinal immune barrier contributes to systemic inflammation and atherosclerosis. Our studies show a causal role of the gut microbiota in the development of systemic inflammation and atherosclerosis. Furthermore, our studies indicate a protective role of the gut immune system and in particular of antimicrobial against development of CVD. Thus our studies indicate that the gut microbiota and the gut immune system may be interesting future targets for the treatment of CVD.
- Published
- 2019
188. C/EBPβ isoforms and the regulation of metabolism: A fine balance between health and disease
- Author
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Ackermann, Tobias, Calkhoven, Cor, de Haan, Gerald, van de Sluis, Bart, and Coffer, Paul J.
- Abstract
Calorie inname en dieet samenstellingen reguleren de eiwit productie en functionaliteit in de cel en oefenen hierdoor een directe invloed uit op de gezondheid en het metabolisme van organismen. Afwijkingen in het metabolisme en verhoogde calorie-inname kunnen leiden tot het ontstaan van metabole ziekten zoals type 2 diabetes en obesitas. Voorheen zijn verschillende factoren geïdentificeerd welke reageren op dieet samenstellingen en calorie-inname en hierdoor een cellulaire respons in gang zetten. In dit proefschrift beschrijven we dat C/EBPβ-LIP een belangrijke factor is die aangestuurd wordt door diëten. C/EBPβ-LIP is een DNA-binding eiwit en vermindert de productie van DNA gecodeerde RNAs en eiwitten om de cellulaire functies te reguleren. Muizen met verminderde hoeveelheden LIP zijn metabool gezonder dan muizen met normale LIP hoeveelheden onder dezelfde diëtaire omstandigheden. Verder beschrijven we hoe verhoogde hoeveelheden LIP resulteert in een metabolisme die vergelijkbaar is met het metabolisme van kanker cellen. We hebben in dit proefschrift LIP geïdentificeerd als factor die gereguleerd wordt door het dieet en de verwerking van voedingsstoffen in de cel veranderd. Om deze reden dragen we LIP voor als belangrijke regulator van lichaamsfuncties, en speculeren we dat een vermindering van LIP door farmacologische inhibitie wellicht kan bijdragen aan de behandeling van metabole ziekten en kanker.
- Published
- 2018
189. Dyslipidemia in the Young: From Genotype to Treatment
- Author
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Balder, Jan-Willem, Kuivenhoven, Jan Albert, Kamphuisen, Pieter Willem, and van de Sluis, Bart
- Abstract
The data presented in this thesis call for: (1) global improvement in the identification of hypercholesterolemia in young individuals by using age- and gender-specific plasma LDL-c levels. These individuals have an increased lifetime risk of CVD – especially those suffering from FH – and personalized advice on lifestyle changes and cholesterol lowering medication should be considered; (2) promotion of the understanding and stimulation of using cardiovascular risk prevention guidelines; and (3) further studies to explore novel pathways implicated in disturbances of LDL metabolism as well as investigate genetic targets like STAP1 that ultimately could lead to improved diagnosis and treatment of dyslipidemia.
- Published
- 2018
190. Mechanistic journeys into lipid metabolism
- Author
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Oldoni, Federico, Kuivenhoven, Jan Albert, Sinke, Richard, and van de Sluis, Bart
- Abstract
Het algemene doel van dit proefschrift betreft de functionele karakterisatie van nieuwe spelers (GPR146) dan wel het ontrafelen van nieuwe rollen van oude spelers (LRP1, ANGPTL3) die betrokken zijn bij dyslipidemie, een gestoorde glucosehuishouding (GALNT2) en/of atherosclerose (LPL, APOA5, LCAT). Er is in dit kader met name aandacht besteed aan moleculaire mechanismes die relevant zijn voor humane ziekebeelden. Hiertoe zijn verschillende benaderingen gebruikt waaronder het uitvoeren van onderzoek in prospectieve humane cohort studies, cellulaire en ook diermodellen.
- Published
- 2017
191. Identification of a novel multiprotein complex in cargo sorting that preserves metabolic pathways in the liver
- Author
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Fedoseienko, Alina and van de Sluis, Bart
- Abstract
Scaffold proteins are crucial regulators of a diverse array of biological processes. This thesis aims to better understand the function of the relatively new family of scaffold proteins called the COMMD proteins. COMMD1, the prototype of this family, has been associated with numerous diseases such as hepatic copper toxicity syndrome, hypercholesterolemia and cancer, but the biological role of the other nine members remains largely unknown. Our study show for the first time that in the liver COMMD6 and COMMD9 both an important role have to preserve cholesterol and copper homeostasis, similarly as we previously demonstrated for COMMD1. Interestingly, however, our data indicate that only myeloid COMMD1 prevents uncontrolled inflammation but not COMMD6 and COMMD9. We show that the COMMD proteins form together a stable multi-COMMD protein complex to regulate these cellular processes. The organization of this complex is likely cell type-specific, but the exact composition of these complexes remains unclear, and more research is wanted. Taken together our work revealed that the COMMD proteins likely act together to facilitate the endosomal trafficking of different transmembrane proteins such as LDLR and ATP7B to preserve cholesterol and copper homeostasis. We expect that better understanding of these pathways will advance therapeutic research to treat hypercholesterolemia and copper disorders.
- Published
- 2016
192. Cellular senescence and inflammation in aging and age-related disease
- Author
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Wijshake, Tobias, Deursen ,van, Jan, van de Sluis, Bart, and Baker, Darren J.
- Abstract
Onze levensverwachting neemt alleen maar toe en helaas gaat dit niet altijd gepaard met gezond ouder worden. Veroudering is namelijk de grootste risicofactor voor de meerderheid van de huidige chronische ziekten zoals diabetes, hart- en vaatziekten en kanker. Het is daarom van belang om het verouderingsproces beter te begrijpen ten einde de levenskwaliteit van de ouderen te verbeteren. Cellulaire senescence is het proces waarin cellen het vermogen verliezen om te delen door een bepaalde stress of schade. Het wordt verondersteld dat deze cellen bijdragen aan veroudering door de stoffen die ze uitscheiden, maar dit was nog niet goed onderzocht. Onze studies tonen aan dat cellulaire senescence bijdraagt aan de ontwikkeling van bepaalde verouderings-gerelateerde ziekten en dat verwijdering van senescent cellen in snel verouderde muizen veroudering in weefsels kan vertragen en de levenskwaliteit kan verbeteren. Daarnaast hebben we aangetoond dat continue hoge BubR1 expressie in muizen de levensverwachting verlengt, de ontwikkeling van tumoren vermindert, en veroudering in bepaalde weefsels vertraagt. In tegenstelling, muizen met een laag BubR1 eiwit niveau hebben een kortere levensduur en ontwikkelen versneld een aantal verouderings-gerelateerde ziekten. Deze studies samen suggereren dat BubR1 een belangrijke regulator is in natuurlijke veroudering in zowel de mens als in de muis. Ten slotte hebben we een andere factor onderzocht die een cruciale speelt in ontstekingsreacties en die daarnaast ook toeneemt bij veroudering. We hebben aangetoond dat een kleine verandering van deze factor de activatie van genen die betrokken zijn bij ontstekingen kan verminderen.
- Published
- 2015
193. New insights into the biological role of COMMD1: from inflammation to steatosis and hypercholesterolemia
- Author
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Bartuzi, Paulina and van de Sluis, Bart
- Abstract
The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) is the prototype of the COMMD family of proteins. It has been shown to regulate various cellular processes, like copper homeostasis, inflammatory response, and hypoxia adaptation, and to mediate the cellular localization of numerous proteins. However, the biological role of COMMD1 and the exact molecular mechanisms by which it regulates these processes are still ill-defined. Therefore, this thesis aimed to give more insight into the biological role of COMMD1 in the pathogenesis of inflammatory diseases, including colitis and non-alcoholic fatty liver disease (NAFLD). The results described in this thesis underline the multifunctional nature of COMMD1, and provide novel insights into its biological function. We demonstrate a cell-type-specific role for COMMD1 in suppressing inflammation, and identify COMMD1 as a novel gene in regulating cholesterol homeostasis and a potential hypercholesterolemia risk gene. Our data indicate that COMMD1 delivers the low-density lipoprotein receptor (LDLR) to the right docking station in the cell. We believe that unraveling the mechanistic action of COMMD1 in the LDLR pathway will help us better understand the mechanism by which COMMD1 regulates biliary copper excretion. Furthermore, our results suggest that hepatic Commd1 plays a role in the progression of high-fat, high-cholesterol (HFC) diet-induced microvesicular steatosis to macrovesicular steatosis. We demonstrated here that microvesicular steatosis is associated with a lower inflammatory tone in the liver and with reduced activation of the LXR pathway, which prevents cells from cholesterol overload. However, further research is necessary to elucidate the mechanism behind this observation. In conclusion, this thesis shows that COMMD1 is a relatively novel adaptor protein in sorting various molecules involved in a number of different biological processes, such as cholesterol and copper homeostasis, and that COMMD1’s role in biological processes is cell-type-specific.
- Published
- 2014
194. COMMD1: a modulator of immunity and NF-kB activity
- Author
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Burstein, Ezra, van de Sluis, Bart, Wijmenga, Cisca, and Research Institute Brain and Cognition (B&C)
- Subjects
Immuunmodulatie ,DNA-bindende eiwitten ,immunologie (geneeskunde) ,infectieziekten, parasitaire ziekten ,Proefschriften (vorm) ,Transcriptiefactoren ,Koperverbindingen ,Ubiquitine - Abstract
Ontsteking is een belangrijk mechanisme van ons lichaam om het te beschermen tegen infecties en beschadiging van weefsels. Deze ontstekingsreactie heeft als doel lichaamsvreemde en beschadigde cellen te verwijderen en te herstellen. Daarentegen kan ongecontroleerde chronische ontsteking veel schade veroorzaken aan weefsel. Om dit te voorkomen is het van belang dat deze ontstekingsreacties op tijd worden stopgezet. De transcriptie factor NF-κB heeft in dit proces een cruciale rol, naast zijn functie in de regulatie van het immuunsysteem. Vanwege zijn centrale rol is de regulatie van deze transcriptie factor zeer intens bestudeerd. De afgelopen jaren is er veel aandacht besteed aan het verkrijgen van inzicht rond het aanzetten van ontstekingsreacties via NF-κB maar er is nog maar weinig bekend over de cellulaire mechanismen en de factoren die betrokken zijn bij het stoppen van ontstekingsreacties. De laatste jaren is men steeds meer te weten gekomen over de rol van ubiquitine-gecontroleerde degradatie van DNA-gebonden NF-κB subunits. Uit dit onderzoek is gebleken dat ubiquitine-gecontroleerde eiwit afbraak een belangrijke rol speelt in het controleren van de expressie van genen tijdens ontstekingsreacties. Het blijkt dat dit mechanisme belangrijk is om de activiteit van NF-κB terug te brengen tot een basaal niveau. Echter was het mechanisme van deze specifieke regulatie nog vrij onbekend. In dit proefschrift tonen we het belang van COMMD1 in dit specifieke proces aan en hebben we de betrokkenheid van COMMD1 in de regulatie van ontstekingsreacties in vivo bestudeerd. Hieronder worden de belangrijkste bevindingen samengevat die beschreven zijn in dit proefschrift. 1) Naast de remming van COMMD1 op NF-κB activiteit, blijkt COMMD1 ook een effect te hebben op de regulatie van HIV-1 replicatie, een proces dat is gekoppeld aan de activiteit van NF-κB in zijn gastheer. Het HIF-1 viraal genoom bevat verschillende κB-sites en via deze sites kan COMMD1 optreden als een factor om de resistentie van naïeve CD4+ cellen tegen HIV-1 replicatie te beïnvloeden. 2) Het mechanisme waarmee COMMD1 de activiteit van NF-κB remt kan toegeschreven worden aan de mogelijkheid om eiwit degradatie van de NF-κB subunit RelA te bevorderen. Dit vindt plaats via de binding van COMMD1 aan NF-κB zelf en aan Cul2. Cul2 is een familielid van de Cullin-RING ligase (CRL) familie en treedt op als een soort “scaffold subunit” binnen dit eiwit-complex. De initiatie van COMMD1-gecontroleerde RelA degradatie vindt plaats op promoter sites van verschillende NF-κB target genen. Het mechanisme hoe COMMD1 naar deze specifieke promoter sites wordt gerekruteerd is nog onbekend. 3) COMMD1 vormde de basis voor de ontdekking van de hele COMMD eiwit familie. Deze familie is zeer sterk geconserveerd tussen verschillende organismen. Ondanks hun gemeenschappelijk carboxyl-terminale COMMD domein, blijkt elke individuele familie lid een specifieke functie te hebben die niet overgenomen kan worden door een ander lid. De functie van de meeste leden, waaronder hun rol in NF-κB regulatie, is nog onduidelijk en moet nog verder worden onderzocht. 4) COMMD1 vormt samen met Cullin een ubiquitine-ligase complex om de mate van RelA ubiquitinatie te bevorderen. COMMD1 bindt aan een gebied binnen het Cullin eiwit dat zeer sterk geconserveerd is binnen de Cullin familie leden. Dit gedeelte van het Cullin eiwit is ook betrokken bij de binding aan CAND1. CAND1 remt op zijn buurt de functie van Cullin-ubiquitine ligase door de binding tussen het substraat (in dit geval RelA) en het Cullin-ubiquitine ligase te verbreken. COMMD1 expressie voorkomt de CAND1 gecontroleerde remming door een competitie aan te gaan met CAND1. Deze gegevens suggereren dat de ubiquitinatie van RelA via COMMD1 wordt bevordert doordat COMMD1 voorkomt dat CAND1 de activiteit van het Cullin-ubiquitne ligase complex remt. 5) Ubiquitinatie van RelA wordt niet alleen via COMMD1 gereguleerd, maar ook via post-translationele modificaties. Met name de fosforylatie van RelA op het aminozuurresidu serine 468 blijkt een belangrijke rol te spelen. Deze post-translationele modificatie wordt gereguleerd via het IKK complex. Dit is het complex dat zorgt voor IκB degradatie en hiermee NF-κB activeert. Dus, het blijkt nu dat via dit mechanisme IKK niet alleen NF-κB activiteit bevordert maar ook NF-κB deactiveert om zo NF-κB terug te brengen naar zijn basale activiteit. 6) De histon acetyltransferase GCN5 zorgt voor een link tussen RelA fosforylatie en ubiquitinatie. In onze studies tonen we aan dat fosforylatie van RelA wordt herkend door GCN5. GCN5 zorgt ervoor dat COMMD1 bindt aan RelA en hiermee de ubiquitinatie gecontroleerde RelA degradatie. Dit effect van GCN is onafhankelijk van zijn histon acetylase activiteit, en heeft dus niks te maken met zijn functie als transcriptie activator. 7) In lijn met zijn functie als NF-κB remmer blijkt COMMD1 een belangrijk rol te hebben als ontstekingsremmer in vivo. Door gebruik te maken van een weefsel specifieke knock-out muis tonen we aan dat muizen deficiënt voor Commd1 in myeloide cellen veel gevoeliger zijn voor ontstekingsreacties, waaronder sepsis. Deze studies laten ook zien dat Commd1 deficiëntie een verhoging in de expressie van NF-κB gecontroleerde genen veroorzaakt, waarbij de mate van RelA ubiquitinatie verlaagd is. Deze studie bevestigt onze bevindingen in cellijnen en laten voor het eerst zien dat COMMD1 ook in vivo belangrijk is om de mate van NF-κB activiteit te controleren. 8) Interessant is dat de mens met chronische ontsteking, zoals patiënten met de ziekte van Crohn, geassocieerd wordt met verlaagde COMMD1 expressie. Met onze knock-out muis modellen laten we een duidelijk correlatie zien tussen verlaagde Commd1 expressie en verhoogde gevoeligheid voor darmontstekingen en geassocieerde darmkanker. Dus onze waarneming dat COMMD1 expressie is verlaagd in patiënten met darmontstekingen is waarschijnlijk maladaptatie en zorgt voor de continuering van de chronische ontstekingen in de darm van deze patiënten. 9) Tot slot, onze studies laten zien dat de reductie in COMMD1 expressie tijdens inflammatoire condities kunnen worden herhaald in cellulaire condities waarbij we het IFN γ route activeren. Hiermee laten we zien dat er een mogelijke link is tussen het paracrine effect van deze cytokine en inflammatoire condities. Daarmee, tonen we een mogelijke “cross-talk” aan tussen de effecten van IFN γ en NF-κB signalering. Samenvattend, dit proefschrift beschrijft de eerste bevindingen en het mechanisme waarmee COMMD1 de mate van NF-κB activiteit controleert. Daarnaast, door middel van muismodellen, bevestigen we de rol van COMMD1 in NF-κB signalering, en dat in de afwezigheid van COMMD1 de inflammatoire status in de verschillende ziektemodellen zeer sterk toeneemt en hierdoor het ziekteproces verslechtert.
- Published
- 2013
195. Cellular Stress in Aging and Cancer
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Ines Sturmlechner, van de Sluis, Bart, and Horazdovsky, B.F.
- Subjects
Stress (mechanics) ,business.industry ,Cancer research ,Medicine ,Cancer ,business ,medicine.disease - Abstract
As our cells and organs are constantly subjected to a multitude of stresses most of which have life-threatening aspects, evolution has selected for sophisticated stress coping mechanisms. While these mechanisms are proficient in stress relief and repair, they are not infallible resulting in morbidities and mortality. Basic and biomedical research have made significant advances in describing stress response genes and pathways on molecular and physiological level, while being also successful in exploiting this knowledge for therapeutic purposes to combat pathologies and diseases. However, due to the variety and complexity of stresses and stress responses, it is still incompletely understood how the fate of cells, cell types, organs and ultimately organisms are shaped and determined by specific stresses. In this thesis, we focus on two major aspects of disease-relevant chronic stress: cellular senescence & aging and aneuploidy & cancer development. We aim to better understand not only their molecular signatures but also their physiological consequences using experimental mouse models. Our gained basic knowledge could help develop novel therapeutic avenues or advance existing strategies to combat aging and age-related diseases including cancer.
196. VLDL Biogenesis and Secretion: It Takes a Village.
- Author
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van Zwol W, van de Sluis B, Ginsberg HN, and Kuivenhoven JA
- Subjects
- Humans, Lipoproteins, Lipoproteins, VLDL, Triglycerides, Liver metabolism, Cholesterol metabolism, Fatty Liver metabolism, Cardiovascular Diseases metabolism
- Abstract
The production and secretion of VLDLs (very-low-density lipoproteins) by hepatocytes has a direct impact on liver fat content, as well as the concentrations of cholesterol and triglycerides in the circulation and thus affects both liver and cardiovascular health, respectively. Importantly, insulin resistance, excess caloric intake, and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. Cholesterol and triglycerides in remnant particles generated by VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease and have garnered increasing attention over the last few decades. Presently, however, increased risk of atherosclerosis is not the only concern when considering today's cardiometabolic patients, as they often also experience hepatic steatosis, a prevalent disorder that can progress to steatohepatitis and cirrhosis. This duality of metabolic risk highlights the importance of understanding the molecular regulation of the biogenesis of VLDL, the lipoprotein that transports triglycerides and cholesterol out of the liver. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL by hepatocytes, which has led to many exciting new molecular insights that are the topic of this review. Increasing our understanding of the biology of this pathway will aid to the identification of novel therapeutic targets to improve both the cardiovascular and the hepatic health of cardiometabolic patients. This review focuses, for the first time, on this duality., Competing Interests: Disclosures None.
- Published
- 2024
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197. Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.
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van Zwol W, Rimbert A, Wolters JC, Smit M, Bloks VW, Kloosterhuis NJ, Huijkman NCA, Koster MH, Tharehalli U, de Neck SM, Bournez C, Fuh MM, Kuipers J, Rajan S, de Bruin A, Ginsberg HN, van Westen GJP, Hussain MM, Scheja L, Heeren J, Zimmerman P, van de Sluis B, and Kuivenhoven JA
- Subjects
- Animals, Female, Humans, Male, Mice, Apolipoproteins B blood, Leucine, Liver metabolism, Triglycerides blood, Atherosclerosis blood, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis prevention & control, Lipoproteins, VLDL biosynthesis, Lipoproteins, VLDL blood, Lipoproteins, VLDL metabolism, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Small Leucine-Rich Proteoglycans genetics, Small Leucine-Rich Proteoglycans metabolism
- Abstract
Background and Aims: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine., Approach and Results: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls., Conclusions: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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198. Mitochondrial DNA methylation in metabolic associated fatty liver disease.
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Mposhi A, Cortés-Mancera F, Heegsma J, de Meijer VE, van de Sluis B, Sydor S, Bechmann LP, Theys C, de Rijk P, De Pooter T, Vanden Berghe W, İnce İA, Faber KN, and Rots MG
- Abstract
Introduction: Hepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD., Methods: HepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients' samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing., Results and Discussion: Differentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mposhi, Cortés-Mancera, Heegsma, de Meijer, van de Sluis, Sydor, Bechmann, Theys, de Rijk, De Pooter, Vanden Berghe, İnce, Faber and Rots.)
- Published
- 2023
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199. Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain.
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Stroo E, Janssen L, Sin O, Hogewerf W, Koster M, Harkema L, Youssef SA, Beschorner N, Wolters AH, Bakker B, Becker L, Garrett L, Marschall S, Hoelter SM, Wurst W, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Thathiah A, Foijer F, van de Sluis B, van Deursen J, Jucker M, de Bruin A, and Nollen EA
- Subjects
- Animals, Humans, Mice, Amyloid beta-Peptides metabolism, Embryonic Development genetics, Mice, Knockout, Brain embryology, Brain metabolism, Intracellular Signaling Peptides and Proteins metabolism, Plaque, Amyloid metabolism
- Abstract
In age-related neurodegenerative diseases, like Alzheimer's and Parkinson's, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm and human cell models for diseases. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated conditional Serf2 knockout mice and found that full-body deletion of Serf2 delayed embryonic development, causing premature birth and perinatal lethality. Brain-specific Serf2 knockout mice, on the other hand, were viable, and showed no major behavioral or cognitive abnormalities. In a mouse model for amyloid-β aggregation, brain depletion of Serf2 altered the binding of structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in the human brain. These results suggest that Serf2 depletion changed the structure of amyloid deposits, which was further supported by scanning transmission electron microscopy, but further study will be required to confirm this observation. Altogether, our data reveal the pleiotropic functions of SERF2 in embryonic development and in the brain and support the existence of modifying factors of amyloid deposition in mammalian brain, which offer possibilities for polymorphism-based interventions., (© 2023 Stroo et al.)
- Published
- 2023
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200. Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.
- Author
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Rutten MGS, Lei Y, Hoogerland JH, Bloks VW, Yang H, Bos T, Krishnamurthy KA, Bleeker A, Koster MH, Thomas RE, Wolters JC, van den Bos H, Mithieux G, Rajas F, Mardinoglu A, Spierings DCJ, de Bruin A, van de Sluis B, and Oosterveer MH
- Abstract
Background: Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia., Methods: Hepatocyte-specific G6pc knockout (L-G6pc
-/- ) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity., Results: Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged., Conclusions: In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
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