Biology subjects

Wewer Albrechtsen, N. J.

Publications and source records attributed to Wewer Albrechtsen, N. J..

6 recordsLinked to original sources

bioRxiv2026

Distribution of the glucagon receptor in periventricular brain barrier interfaces including motile and primary cilia in rat brain

Glucagon is a key metabolic hormone regulating blood glucose and appetite, yet little is known about its actions within the brain. Here, we investigated its receptor (GCGR) localization in periventricular brain barrier interfaces in young rats using immunohistochemical and immunofluorescence approaches. GCGR was enriched in the proximal region of motile ependymal cilia lining the ventricles, as well as in tanycytic primary cilia and cytoplasmic extensions within the hypothalamus. Additional immunostaining was observed in ciliated cells of the subcommissural organ and, more heterogeneously, in choroid plexus epithelium and associated primary cilia, while other circumventricular organs lacked detectable GCGR. These findings identify brain cilia and tanycytes as previously unrecognized sites of glucagon receptor localization and suggest that glucagon signaling at brain barrier interfaces may contribute to integrating peripheral metabolic cues with central homeostatic circuits.

neuroscience↗

bioRxiv2022

Dynamic human liver proteome atlas reveals functional insights into disease pathways

Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell-type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time-course of primary cell cultures and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serves as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactively exploration of our resource. HighlightsO_LICell-type resolved liver proteome with copy numbers for 10,500 proteins C_LIO_LITime-course of human liver primary cells uncovers functional proteome shifts C_LIO_LIA human cohort study reveals liver proteome changes in NASH and cirrhosis C_LIO_LIAn interactive web portal integrates the results for easy exploration C_LI

systems biology↗

bioRxiv2021

Evaluation of Commercially Available Glucagon Receptor Antibodies and Glucagon Receptor Expression

Glucagon is a key regulator of numerous metabolic functions including glucose, protein and lipid metabolism, and glucagon-based therapies are explored for diabetes, fatty liver disease and obesity. Insight into tissue and cell specific expression of the glucagon receptor (GCGR) is important to understand the biology of glucagon as well as to differentiate between direct and indirect actions of glucagon. However, it has been challenging to accurately localize the GCGR in tissue due to low expression levels and lack of specific methodologies. Immunohistochemistry has frequently been used for GCGR localization, but G-protein-coupled receptors (GPCRs) targeting antibodies are notoriously unreliable. In this study, we systematically evaluated all commercially available GCGR antibodies. Initially, twelve GCGR antibodies were evaluated using HEK293 cells transfected with mouse or human GCGR cDNA. Of the twelve antibodies tested, eleven showed positive staining of GCGR protein from both species. Human liver tissue was investigated using the same GCGR antibodies. Five antibodies failed to stain human liver biopsies (despite explicit claims to the contrary from the vendors). Immunohistochemical (IHC) staining demonstrated positive staining of liver tissue from glucagon receptor knockout (Gcgr-/-) mice and their wild-type littermates (Gcgr+/+) with only one out of the twelve available GCGR antibodies. Three antibodies were selected for further evaluation by western blotting and bands corresponding to the predicted size of the GCGR (62 kDa) were identified using two of these. Finally, a single antibody (no. 11) was selected for specific GCGR localization studies in various tissues. In mouse tissue the most intense immunostainings were found in lever, kidney, ileum, heart, and pancreas. Western blotting, performed on liver tissue from Gcgr+/+ and Gcgr-/- mice, confirmed the specificity of antibody no. 11, detecting a band at high intensity in material from Gcgr+/+and no bands in liver tissue from Gcgr-/-mice. Staining of human kidney tissue, with antibody no. 11, showed GCGR localization to the distal tubules. Autoradiography was used as an antibody-independent approach to support the antibody-based findings, revealing specific binding in liver, pancreas, and kidney. As a final approach, RNA-sequencing and single-cell RNA (scRNA)-sequencing were implemented. RNA-sequencing confirmed GCGR presence within liver and kidney tissue. The GCGR was specifically found to be expressed in hepatocytes by scRNA-sequencing and potentially also in collecting and distal tubule cells in the kidney. Our results clearly indicate the liver and the kidneys as the primary targets of glucagon action.

physiology↗

bioRxiv2020

Clinical Knowledge Graph Integrates Proteomics Data into Clinical Decision-Making

The promise of precision medicine is to deliver personalized treatment based on the unique physiology of each patient. This concept was fueled by the genomic revolution, but it is now evident that integrating other types of omics data, like proteomics, into the clinical decision-making process will be essential to accomplish precision medicine goals. However, quantity and diversity of biomedical data, and the spread of clinically relevant knowledge across myriad biomedical databases and publications makes this exceptionally difficult. To address this, we developed the Clinical Knowledge Graph (CKG), an open source platform currently comprised of more than 16 million nodes and 220 million relationships to represent relevant experimental data, public databases and the literature. The CKG also incorporates the latest statistical and machine learning algorithms, drastically accelerating analysis and interpretation of typical proteomics workflows. We use several biomarker studies to illustrate how the CKG may support, enrich and accelerate clinical decision-making. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/084897v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@433689org.highwire.dtl.DTLVardef@b18068org.highwire.dtl.DTLVardef@1656084org.highwire.dtl.DTLVardef@a38201_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2019

Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice

AimTo identify the amino acids that stimulate glucagon secretion in mice and whether the metabolism of these relies on glucagon receptor signaling.\n\nMethodsPancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids (1 mM) and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25-2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice three hours prior to an intraperitoneal injection of four different isomolar (in total 7 {micro}mol/g body weight) amino acid mixtures; mixture 1: alanine, arginine, cysteine, and proline; mixture 2: asparatate, glutamate, histidine, and lysine; mixture 3: citrulline, methionine, serine, and threonine; and mixture 4: glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well characterized methodologies.\n\nResultsAlanine (P=0.03), arginine (P<0.001), and proline (P=0.03) but not glutamine (P=0.2) stimulated glucagon secretion from the perfused mouse pancreas. Cysteine had the numerically largest effect on glucagon secretion but did not reach statistical significance (P=0.08). However, when the four isomolar amino acid mixtures were administered there were no significant difference (P>0.5) in plasma concentrations of glucagon across mixture 1-4. Plasma concentrations of total amino acids were higher after administration of GRA when mixture 1 (P=0.004) or mixture 3 (P=0.04) were injected.\n\nConclusionOur data suggest that alanine, arginine, and proline but not glutamine are involved in the liver-alpha cell axis in mice as they all increased glucagon secretion and their disappearance rate was altered by GRA.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC=\"FIGDIR/small/792119v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (19K):\norg.highwire.dtl.DTLVardef@b78a3corg.highwire.dtl.DTLVardef@1d475d1org.highwire.dtl.DTLVardef@1830a00org.highwire.dtl.DTLVardef@59c51_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Secretin release after Roux-en-Y Gastric Bypass reveals a population of glucose-sensitive S-cells in distal small intestine

ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.\n\nMethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation.\n\nResultsPlasma postprandial secretin was more than doubled in humans after RYGB (P<0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased secretion of secretin in a sodium-glucose co-transporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P<0.05) from the perfused rat pancreas but affected neither insulin (P=0.2) nor glucagon (P=0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P=0.04), while blood glucose peak time was delayed (from 15 min to 45 min) and gastric emptying time prolonged (P=0.004).\n\nConclusionGlucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S-cells warrants further studies.

physiology↗