ORCID Profile
0000-0002-0197-3010
Current Organisations
IT University of Copenhagen
,
Københavns Universitet
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Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2022
DOI: 10.1101/2022.02.08.479601
Abstract: Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored cell adhesion molecule encoded by an obesity susceptibility gene. We demonstrate that NEGR1 accumulates in GABAergic inhibitory synapses in hypothalamic neurons, a GABA-synthesizing enzyme GAD65 attaches to the plasma membrane, and NEGR1 promotes clustering of GAD65 at the synaptic plasma membrane. GAD65 is removed from the plasma membrane with newly formed vesicles. The association of GAD65 with vesicles results in increased GABA synthesis. In NEGR1 deficient mice, the synaptic targeting of GAD65 is decreased, the GABAergic synapse densities are reduced, and the reinforcing effects of food rewards are blunted. In mice fed a high fat diet, levels of NEGR1 are increased and GAD65 abnormally accumulates at the synaptic plasma membrane. Our results indicate that NEGR1 regulates a previously unknown step required for synaptic targeting and functioning of GAD65, which can be affected by bidirectional changes in NEGR1 levels causing disruptions in the GABAergic signaling controlling feeding behavior.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1194/JLR.M040451
Publisher: Wiley
Date: 08-12-2014
Publisher: MDPI AG
Date: 25-12-2018
DOI: 10.3390/IJMS20010074
Abstract: Human exonuclease 1 (EXO1), a 5′→3′ exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication stress and potential collapse of the replication fork. Failure to restart the DNA replication process can result in double-strand breaks, cell-cycle arrest, cell death, or cellular transformation. In this review, we summarize the involvement of EXO1 in the replication, DNA repair pathways, cell cycle checkpoints, and the link between EXO1 and cancer.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2019
Publisher: Georg Thieme Verlag KG
Date: 29-09-2016
Abstract: The pathways through which fatty acids induce insulin resistance have been the subject of much research. We hypothesise that by focussing on the reversal of insulin resistance, novel insights can be made regarding the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered during the prevention of palmitate-induced glucose production in hepatocytes using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075 mM, 48 h) with or without metformin (0.25 mM) and sodium salicylate (2 mM) in the final 24 h of palmitate treatment, and effects on glucose production were determined. RNA microarray measurements followed by gene set enrichment analysis were performed to investigate pathway regulation. Lipidomic analysis and measurement of secreted bile acids and cholesterol were also performed. Reversal of palmitate-induced glucose production by metformin and sodium salicylate was characterised by co-ordinated down-regulated expression of pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. All 20 enzymes that regulate the conversion of acetyl-CoA to cholesterol were reduced following metformin and sodium salicylate. Selected findings were confirmed using primary mouse hepatocytes. Although total intracellular levels of diacylglycerol, triacylglycerol and cholesterol esters increased with palmitate, these were not, however, further altered by metformin and sodium salicylate. 6 in idual diacylglycerol, triacylglycerol and cholesterol ester species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. These results implicate acetyl-CoA metabolism and C18 lipid species as modulators of hepatic glucose production that could be targeted to improve glucose homeostasis.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.FREERADBIOMED.2016.04.197
Abstract: Mitochondria play a critical role in energy production, cell signalling and cell survival. Defects in mitochondrial function contribute to the ageing process and ageing-related disorders such as metabolic disease, cancer, and neurodegeneration. The sirtuin family of deacylase enzymes have a variety of subcellular localisations and have been found to remove a growing list of post-translational acyl modifications from target proteins. SIRT3, SIRT4, and SIRT5 are found primarily located in the mitochondria, and are involved in many of the key processes of this organelle. SIRT3 has been the subject of intense research and is primarily a deacetylase thought to function as a mitochondrial fidelity protein, with roles in mitochondrial substrate metabolism, protection against oxidative stress, and cell survival pathways. Less is known about the functional targets of SIRT4, which has deacetylase, ADP-ribosylase, and a newly-described lipoamidase function, although key roles in lipid and glutamine metabolism have been reported. SIRT5 modulates a host of newly-discovered acyl modifications including succinylation, malonylation, and glutarylation in both mitochondrial and extra-mitochondrial compartments, however the functional significance of SIRT5 in the regulation of many of its proposed target proteins remains to be discovered. Because of their influence on a broad range of pathways, SIRT3, SIRT4, and SIRT5 are implicated in a range of disease-states including metabolic disease such as diabetes, neurodegenerative diseases, cancer, and ageing-related disorders such as hearing-loss and cardiac dysfunction. We review the current knowledge on the function of the three mitochondrial sirtuins, their role in disease, and the current outstanding questions in the field.
Publisher: Portland Press Ltd.
Date: 02-10-2015
DOI: 10.1042/BJ20150602
Abstract: Null mutations of the Niemann–Pick type C1 (NPC1) gene cause NPC disease, a lysosomal storage disorder characterized by cholesterol accumulation in late endosomes (LE) and lysosomes (Ly). Nascent or mutated NPC1 is degraded through the ubiquitin–proteasome pathway, but how NPC1 degradation is regulated remains currently unknown. In the present study, we demonstrated a link between NPC1 degradation and the Akt (protein kinase B)/mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway in cervical cancer cell lines. We provided evidence that activated Akt/mTOR pathway increased NPC1 degradation by ∼50% in C33A cells when compared with SiHa or HeLa cells. NPC1 degradation in C33A cells was reversed when Akt/mTOR activation was blocked by specific inhibitors or when mTORC1 (mTOR complex 1) was disrupted by regulatory associated protein of mTOR (Raptor) knockdown. Importantly, inhibition of the Akt/mTOR pathway led to decreased NPC1 ubiquitination in C33A cells, pointing to a role of Akt/mTOR in the proteasomal degradation of NPC1. Moreover, we found that NPC1 depletion in several cancer cell lines inhibited cell proliferation and migration. Our results uncover Akt as a key regulator of NPC1 degradation and link NPC1 to cancer cell proliferation and migration.
Publisher: MDPI AG
Date: 18-11-2020
DOI: 10.3390/MOLECULES25225392
Abstract: Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is a pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles in steatosis, insulin resistance, cancers and inflammatory and fibrotic diseases. In addition, DPP4 binds to the spike protein of the MERS virus, causing it to be the human cell surface receptor for that virus. DPP4 has been identified as a potential binding target of SARS-CoV-2 spike protein, so this question requires experimental investigation. Understanding protein structure and function requires reliable protocols for production and purification. We developed such strategies for baculovirus generated soluble recombinant human DPP4 (residues 29–766) produced in insect cells. Purification used differential ammonium sulphate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in series with immobilised metal affinity chromatography, and ion-exchange chromatography. The binding affinities of DPP4 to the SARS-CoV-2 full-length spike protein and its receptor-binding domain (RBD) were measured using surface plasmon resonance and ELISA. This optimised DPP4 purification procedure yielded 1 to 1.8 mg of pure fully active soluble DPP4 protein per litre of insect cell culture with specific activity U/mg, indicative of high purity. No specific binding between DPP4 and CoV-2 spike protein was detected by surface plasmon resonance or ELISA. In summary, a procedure for high purity high yield soluble human DPP4 was achieved and used to show that, unlike MERS, SARS-CoV-2 does not bind human DPP4.
Publisher: Cold Spring Harbor Laboratory
Date: 09-03-2022
DOI: 10.1101/2022.03.08.483430
Abstract: There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csb m/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.
Publisher: MDPI AG
Date: 08-06-2019
DOI: 10.3390/JCM8060822
Abstract: The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.
Publisher: Wiley
Date: 20-05-2020
DOI: 10.1111/APHA.13455
Publisher: Springer Science and Business Media LLC
Date: 15-08-2022
DOI: 10.1038/S43587-022-00263-3
Abstract: Cellular senescence is an important factor in aging and many age-related diseases, but understanding its role in health is challenging due to the lack of exclusive or universal markers. Using neural networks, we predict senescence from the nuclear morphology of human fibroblasts with up to 95% accuracy, and investigate murine astrocytes, murine neurons, and fibroblasts with premature aging in culture. After generalizing our approach, the predictor recognizes higher rates of senescence in p21-positive and ethynyl-2’-deoxyuridine (EdU)-negative nuclei in tissues and shows an increasing rate of senescent cells with age in H& E-stained murine liver tissue and human dermal biopsies. Evaluating medical records reveals that higher rates of senescent cells correspond to decreased rates of malignant neoplasms and increased rates of osteoporosis, osteoarthritis, hypertension and cerebral infarction. In sum, we show that morphological alterations of the nucleus can serve as a deep learning predictor of senescence that is applicable across tissues and species and is associated with health outcomes in humans.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2018
DOI: 10.1038/S41467-018-05613-7
Abstract: Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.
Publisher: Rockefeller University Press
Date: 25-10-2020
Abstract: Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in cellular metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. During LD biogenesis and growth, this monolayer of lipids expands by acquiring phospholipids from the endoplasmic reticulum (ER) through nonvesicular mechanisms. Here, in a mini-screen, we find that ORP5, an integral membrane protein of the ER, can localize to ER–LD contact sites upon oleate loading. ORP5 interacts with LDs through its ligand-binding domain, and ORP5 deficiency enhances neutral lipid synthesis and increases the size of LDs. Importantly, there is significantly more phosphatidylinositol-4-phosphate (PI(4)P) and less phosphatidylserine (PS) on LDs in ORP5-deficient cells than in normal cells. The increased presence of PI(4)P on LDs in ORP5-deficient cells requires phosphatidylinositol 4-kinase 2-α. Our results thus demonstrate the existence of PI(4)P on LDs and suggest that LD-associated PI(4)P may be primarily used by ORP5 to deliver PS to LDs.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.TIPS.2016.01.007
Abstract: Despite major investment by pharmaceutical companies in conventional drug discovery pipelines, development of new drugs has failed to keep up with the increasing incidence of many diseases, including type 2 diabetes (T2D). Drug repurposing, where existing drugs are applied to a new indication, is gaining momentum as a successful approach to overcome the bottlenecks commonly encountered with conventional approaches. Repurposing takes advantage of available information on the molecular pharmacology of clinical agents to drastically shorten drug development timelines. This review discusses recent advances in the discovery of new antidiabetic agents using repurposing strategies.
Publisher: Wiley
Date: 10-2017
DOI: 10.1111/JNE.12508
Abstract: Nicotinamide adenine dinucleotide (NAD
Publisher: Impact Journals, LLC
Date: 30-12-2020
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BBAGEN.2013.08.016
Abstract: In recent years, reversible lysine acylation of proteins has emerged as a major post-translational modification across the cell, and importantly has been shown to regulate many proteins in mitochondria. One key family of deacylase enzymes is the sirtuins, of which SIRT3, SIRT4, and SIRT5 are localised to the mitochondria and regulate acyl modifications in this organelle. In this review we discuss the emerging role of lysine acylation in the mitochondrion and summarise the evidence that proposes mitochondrial sirtuins are important players in the modulation of mitochondrial energy metabolism in response to external nutrient cues, via their action as lysine deacylases. We also highlight some key areas of mitochondrial sirtuin biology where future research efforts are required. Lysine deacetylation appears to play some role in regulating mitochondrial metabolism. Recent discoveries of new enzymatic capabilities of mitochondrial sirtuins, including desuccinylation and demalonylation activities, as well as an increasing list of novel protein substrates have identified many new questions regarding the role of mitochondrial sirtuins in the regulation of energy metabolism. Dynamic changes in the regulation of mitochondrial metabolism may have far-reaching consequences for many diseases, and despite promising initial findings in knockout animals and cell models, the role of the mitochondrial sirtuins requires further exploration in this context. This article is part of a Special Issue entitled Frontiers of mitochondrial research.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Bioscientifica
Date: 19-06-2023
DOI: 10.1530/JOE-22-0101
Abstract: Reduced expression of the NAD + -dependent deacetylase, SIRT3, has been associated with insulin resistance and metabolic dysfunction in humans and rodents. In this study, we investigated whether specific overexpression of SIRT3 in vivo in skeletal muscle could prevent high-fat diet (HFD)-induced muscle insulin resistance. To address this, we used a muscle-specific adeno-associated virus (AAV) to overexpress SIRT3 in rat tibialis and extensor digitorum longus (EDL) muscles. Mitochondrial substrate oxidation, substrate switching and oxidative enzyme activity were assessed in skeletal muscles with and without SIRT3 overexpression. Muscle-specific insulin action was also assessed by hyperinsulinaemic–euglycaemic cl s in rats that underwent a 4-week HFD-feeding protocol. Ex vivo functional assays revealed elevated activity of selected SIRT3-target enzymes including hexokinase, isocitrate dehydrogenase and pyruvate dehydrogenase that was associated with an increase in the ability to switch between fatty acid- and glucose-derived substrates in muscles with SIRT3 overexpression. However, during the cl , muscles from rats fed an HFD with increased SIRT3 expression displayed equally impaired glucose uptake and insulin-stimulated glycogen synthesis as the contralateral control muscle. Intramuscular triglyceride content was similarly increased in the muscle of high-fat-fed rats, regardless of SIRT3 status. Thus, despite SIRT3 knockout (KO) mouse models indicating many beneficial metabolic roles for SIRT3, our findings show that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats.
Publisher: Elsevier
Date: 2019
Publisher: The Royal Society of Chemistry
Date: 30-11-2011
DOI: 10.1039/9781849733151-00118
Abstract: In recent years, the dipeptidyl peptidase-4 (DPP-4) enzyme family has created intense pharmaceutical interest. DPP-4 inhibitors have proven successful as a therapy for the growing type 2 diabetes epidemic and have potential to treat other diseases. A large number of recently developed DPP-4 inhibitors are in various phases of clinical development, with four gliptin class inhibitors already in clinical use. The unique distribution of Fibroblast Activation Protein (FAP), the closest relative of DPP-4, has led to numerous investigations of it as a target and marker for epithelial cancers. The roles of the newer members, DPP-8 and DPP-9, are yet to be fully characterized, but early evidence suggests possible roles in various aspects of cell biology and disease. There are a number of favorable circumstances that have contributed to the therapeutic approaches of targeting DPP-4 and FAP. Specific targeting of DPP-4 and FAP is made easier by the small size of this enzyme family and several structural differences at their active sites. Additionally, observations over the past decade that the DPP-4 and FAP gene knockout mice are healthy suggests that selective inhibition of each of these proteases would be safe, and this is reflected in the excellent safety profiles of the DPP-4-selective gliptins. These proteins also have interesting extra-enzymatic activities that are expected to be retained in the presence of protease inhibition. This feature also points to a low likelihood of off-target effects. Thus, an overall understanding of DPP-4 and FAP structure–function relationships, distribution, and enzymatic and extra-enzymatic biological roles provides an insight into their therapeutic usefulness as disease targets.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BBRC.2022.03.088
Abstract: The mitochondrial enzyme SIRT3 is an NAD
Start Date: 2011
End Date: 2014
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2019
Funder: Hartmann Fonden
View Funded ActivityStart Date: 2019
End Date: 2020
Funder: Fonden til Lægevidenskabens Fremme
View Funded Activity