A5001579079- Pancreatic function and diabetes
- Cellular transport and secretion
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Liver Disease Diagnosis and Treatment
- RNA Interference and Gene Delivery
- Endoplasmic Reticulum Stress and Disease
- Biomedical Research and Pathophysiology
- Diabetes Treatment and Management
- Adipokines, Inflammation, and Metabolic Diseases
- Erythrocyte Function and Pathophysiology
- Calcium signaling and nucleotide metabolism
- Lipid metabolism and biosynthesis
- Advanced biosensing and bioanalysis techniques
- Cancer-related molecular mechanisms research
- Diet, Metabolism, and Disease
- Cell Adhesion Molecules Research
- Lipid Membrane Structure and Behavior
- Diet and metabolism studies
- Cancer, Hypoxia, and Metabolism
- Microtubule and mitosis dynamics
- Pharmacogenetics and Drug Metabolism
- Drug-Induced Hepatotoxicity and Protection
- Lipid metabolism and disorders
- Diabetes and associated disorders
University Hospital Heidelberg
2017-2024
Heidelberg University
2001-2024
Heinrich Heine University Düsseldorf
2016-2024
Deutsches Diabetes-Zentrum e.V.
2016-2024
Helmholtz Zentrum München
2016-2024
German Center for Diabetes Research
2016-2024
Technical University of Munich
2022
Heidelberg (Poland)
2021
Max Planck Institute of Molecular Cell Biology and Genetics
2010-2017
Max Planck Society
2012
Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) hepatocytes in vivo; however, the precise mechanism by which this delivery occurs has yet elucidated. We found that apolipoprotein E (apoE), plays a major role clearance and hepatocellular uptake physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic (cLNPs). The apoE was investigated using both vitro studies employing...
Insulin maintains whole body blood glucose homeostasis, in part, by regulating the amount of GLUT4 transporter on cell surface fat and muscle cells. induces redistribution from intracellular compartments to plasma membrane, stimulating a large increase exocytosis smaller inhibition endocytosis. A considerable is known about molecular events insulin signaling complex itinerary trafficking, but less how transmitted trafficking. Here, we show that AS160 RabGAP, substrate Akt, required for...
Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or determination an acceptable daily intake (ADI). To overcome this limitation, vitro/in silico method was established that predicts risk human DILI relation to oral and blood concentrations. This can used estimate if maximal concentration (Cmax) test compound is known. Moreover, ADI estimated even compounds...
We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, GLP-1/GIP dual-agonists MAR709 tirzepatide. Receptor G protein recruitment internalization/trafficking were using bioluminescence resonance energy transfer (BRET)-based technology live-cell HILO microscopy. Relative to native acylated agonists, tirzepatide showed preserved maximal cAMP production despite partial Gαs paralleled by...
The intracellularly stored GLUT4 glucose transporter is rapidly translocated to the cell surface upon insulin stimulation. Regulation of distribution key for maintenance whole body homeostasis. We find that excluded from plasma membrane adipocytes by a dynamic retention/retrieval mechanism. Our kinetic studies indicate GLUT4-containing vesicles continually bud and fuse with endosomes in absence these are 5 times as likely an endosome membrane. hypothesize this intracellular cycle vesicle...
Insulin regulates glucose uptake into fat and muscle by modulating the distribution of GLUT4 transporter between surface interior cells. The trafficking pathway overlaps with general endocytic recycling pathway, but degree functional significance overlap are not known. In this study intact adipocytes, we demonstrate, using a compartment-specific fluorescence-quenching assay, that is equally distributed two intracellular pools: transferrin receptor-containing endosomes specialized compartment...
Exploring the cell biology of hepatocytes in vitro could be a powerful strategy to dissect molecular mechanisms underlying structure and function liver vivo. However, this approach relies on appropriate culture systems that can recapitulate biological metabolic features whilst being accessible experimental manipulations. Here, we adapted protocols for high-resolution fluorescence microscopy quantitative image analysis compare two primary hepatocyte systems, monolayer collagen sandwich, with...
Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve is identify molecules enhancing these steps. It unclear what extent such enhancers can be universally applied different cell types. Here, we performed a compound library screen two well-established siRNA systems, lipid nanoparticles cholesterol conjugated-siRNAs. We identified fifty-one improving gene silencing 2–5 fold. Strikingly, most...
Abstract Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 which features elevated blood glucose levels and an inability to adequately secrete or respond insulin. Insulin producing β-cells have primary cilia are implicated the regulation of metabolism, insulin signaling secretion. To better understand how β-cell affect handling, we ablate mature by deleting key component Ift88 . Here report that homeostasis secretion deteriorate over 12 weeks post-induction....
Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for ability directly act on the liver de novo glucose production and inhibit glycogen breakdown, lowers body weight by decreasing food intake increasing rate. Glucagon further promotes lipolysis lipid oxidation has positive chronotropic inotropic effects in heart. Interestingly, recent decades have witnessed...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic disease. Owing to limited available treatment options, novel pre-clinical models for target selection and drug validation are warranted. We have established extensively characterized a primary human hepatocyte in vitro model system that could guide development strategies MASLD.
In several cell types, specific membrane proteins are retained intracellularly and rapidly redistributed to the surface in response stimulation. fat muscle, GLUT4 glucose transporter is dynamically because it internalized slowly recycled plasma membrane. Insulin increases recycling of GLUT4, resulting a net translocation surface. We have shown that fibroblasts also an insulin-regulated mechanism. Here we show within transferrin receptor-containing general endosomal compartment Chinese...
The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of organism. Communication between hepatocytes extracellular environment via endocytosis is key such homeostasis. Here, we addressed question whether endosomes are required for gluconeogenic gene expression. We took advantage loss in mouse upon Rab5 silencing. Strikingly, found hepatomegaly severe defects as hypoglycemia, hypercholesterolemia, hyperlipidemia, glycogen accumulation that...
In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance mortality rates. However, such morphological phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the landscape seen murine human PDAC, pronounced molecular is governed defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity),...