Biology subjects

Odermatt, A.

Publications and source records attributed to Odermatt, A..

10 recordsLinked to original sources

bioRxiv2026

Hexose-6-phosphate dehydrogenase deficiency disrupts hepatic fatty acid homeostasis and induces triglyceride accumulation

Hexose-6-phosphate dehydrogenase (H6PD) catalyzes the first two steps of an endoplasmic reticulum-specific pentose phosphate pathway, regenerating luminal NADPH levels in the process. Its function remains insufficiently well understood. Since expression of H6PD is notably high in the liver, we aimed to assess its role in hepatic metabolism. Considering the central role of the liver in lipid synthesis, breakdown and storage, we focused our efforts specifically on studying the effect of H6PD on hepatic lipid metabolism. An H6PD knockout mice strain was generated and characterized by liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based lipidomic and proteomic analyses of liver tissue. Lipidomics analysis revealed an overall increase in hepatic triglycerides and a specific increase in unsaturated long-chain triglycerides in H6PD knockout mice. Intracellular lipid accumulation was confirmed through Nile Red staining of liver sections. Functional enrichment analysis of proteomics data from the H6PD deficient mice identified a corresponding upregulation of multiple fatty acid metabolism-associated pathways. Additionally, an H6PD knockout AML12 cell line was generated through CRISPR/Cas9 and characterized by lipid staining and functional assays to assess metabolic outcomes. Loss of H6PD led to intracellular lipid accumulation, reduced mitochondrial {beta}-oxidation and increased sensitivity to lipotoxicity, even though fatty acids remained the cells' primary mitochondrial fuel. Ultimately, our results indicate that H6PD plays an as-of-yet undescribed role in hepatic lipid metabolism, implying a link between the availability of NADPH within the endoplasmic reticulum and fatty acid homeostasis.

systems biology↗

bioRxiv2026

Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

11{beta}-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.

microbiology↗

bioRxiv2025

Alterations in glucocorticoid homeostasis following sleeve gastrectomy

Elevated intra-tissue levels of active glucocorticoids in obese patients are associated with insulin resistance, diabetes, impaired immune regulation, and other adverse effects. Sleeve gastrectomy (SG) induces significant weight loss and improves metabolic outcomes, including insulin resistance and hyperlipidemia. Among the enzymes controlling intracellular concentrations of active glucocorticoids, 11{beta}-hydroxysteroid dehydrogenase type 1 (HSD11B1, SDR26C1) has been extensively studied concerning obesity and post-gastric surgery interventions. However, most studies focused on either a single tissue, circulating glucocorticoid levels, or HSD11B1 activity. In this work, we showed that circulating active/inactive glucocorticoid ratio (corticosterone (B)/11-dehydrocorticosterone (A)) negatively correlated with glucose tolerance; SG in male C57BL/6 mice slightly reduced circulating mineralocorticoids and reversed the elevated ratio of B/A seen in sham-operated mice after high-fat diet, while improving glucose tolerance. This change was likely due to increased renal 11{beta}-hydroxysteroid dehydrogenase type 2 (HSD11B2, SDR9C3) activity after SG. To provide a comprehensive overview of the systemic effects post-surgery, we evaluated enzymes involved in glucocorticoid homeostasis across tissues on mRNA, protein, and activity level. Moreover, mRNA expression of transcription factors CCAAT enhancer binding protein alpha (Cebpa), Cebpb and nuclear factor kappa b (Nf{kappa}b (p50)), as well as cytokines influencing Hsd11b1 and Hsd11b2 gene expression were analyzed. The results emphasize stronger influence of renal HSD11B2 than hepatic HSD11B1 activity on the circulating B/A ratio, supported by intrarenal and intrahepatic B/A ratios. The improved glucocorticoid homeostasis following SG, indicated by decreased B/A ratios, proposes a lower risk for glucocorticoid-mediated adverse health effects, including chronic kidney disease, hypertension, and metabolic disturbances. NEW & NOTEWORTHYThis study revealed improved glucocorticoid homeostasis after sleeve gastrectomy (SG), with lower circulating ratios of active (corticosterone, B)/inactive (11-dehydrocorticosterone, A) glucocorticoids and a better glucose tolerance compared to Sham mice. SG enhanced renal HSD11B2 activity, while hepatic HSD11B1 oxoreductase activity was unchanged. These findings suggest that SG reverses some adverse metabolic effects of high-fat diet by enhancing renal HSD11B2 activity, potentially lowering the risk of chronic kidney disease, hypertension, and metabolic disease.

physiology↗

bioRxiv2025

Tissular glucocorticoid reactivating enzyme 11beta-HSD1 drives pathogenic myofibroblast differentiation in chronic kidney disease

Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality and morbidity. Irrespective of its underlying cause, tubulointerstitial fibrosis (TIF) is a hallmark of CKD progression, with myofibroblasts being the primary effectors of renal fibrosis. Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11{beta}-HSD1) is a critical driver of pathogenic myofibroblast differentiation and fibrosis in CKD. Using genetic deletion and pharmacological inhibition of 11{beta}-HSD1 in mouse models, we demonstrate a marked reduction in TIF severity and improved renal function, linked to the suppression of a regulatory myofibroblast (Reg-MF) subpopulation. Single-cell and spatial transcriptomics data reveal that 11{beta}-HSD1 is essential for the activation and expansion of Reg-MFs, which is conserved across species and predicts worse outcomes in CKD patients and kidney allograft recipients. These findings establish a direct link between 11{beta}-HSD1 activity and renal fibrogenesis, highlighting its role during the transition from pericytes to pathogenic Reg-MFs. Our results support 11{beta}-HSD1 inhibition as a promising therapeutic strategy to mitigate CKD progression, offering both mechanistic insights and translational potential for improving patient outcomes.

physiology↗

bioRxiv2024

Advanced Tissue Technologies of Blood-Brain Barrier Organoids as High Throughput Toxicity Readouts in Drug Development

Recent advancements in engineering Complex in vitro models (CIVMs) such as Blood-brain barrier (BBB) organoids offer promising platforms for preclinical drug testing. However, their application in drug development, and especially for the regulatory purposes of toxicity assessment, requires robust and reproducible techniques. Here, we developed an adapted set of orthogonal image-based tissue methods including hematoxylin and eosin staining (HE), immunohistochemistry (IHC), multiplex immunofluorescence (mIF), and Matrix Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) to validate CIVMs for drug toxicity assessments. We developed an artificial intelligence (AI) algorithm to increase the throughput and the reliability of histomorphologic evaluations of apoptosis for in vitro toxicity studies. Our data highlight the potential to integrate advanced morphology-based readouts such as histological techniques and digital pathology algorithms for use on CIVMs, as part of a standard preclinical drug development assessment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/611987v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@190530eorg.highwire.dtl.DTLVardef@3cce5forg.highwire.dtl.DTLVardef@10ec3borg.highwire.dtl.DTLVardef@1051585_HPS_FORMAT_FIGEXP M_FIG C_FIG The graphical abstract was partially created with biorender.com. HighlightsO_LIAdvanced Complex in vitro models (CIVMs) like Blood-brain barrier (BBB) organoids show promise for preclinical drug testing. However, robust and reproducible techniques are crucial for the acceptance of CIVMs in drug development processes, especially for toxicity assessments which are highly regulated by health authorities. C_LIO_LIWe developed orthogonal image-based readouts on histological sections to enable the use of BBB organoids for future compound toxicity assessment. C_LIO_LIA newly established artificial intelligence (AI) algorithm provides automated and label-free detection of apoptotic cells in drug screening using BBB organoids and provides an alternative killing assay on single cell resolution (40x) to current standards. C_LI

pathology↗

bioRxiv2024

ApoE4 disrupts intracellular trafficking and iron homeostasis in an improved iPSC-based model of human brain endothelial cells

Transferrin receptor in brain endothelial cells can deliver therapeutic antibodies to the brain via transcytosis across the blood-brain barrier. Whether receptor transport remains intact in Alzheimers disease is still a major open question. Here, we investigated whether apolipoprotein E4 (ApoE4), the major genetic risk factor for Alzheimers disease, altered intracellular transport in human brain endothelial cells. To achieve this, we first developed an optimized protocol for induced pluripotent stem cells based on a defined chemical cocktail and extracellular-matrix support to differentiate brain endothelial cells (iCE-BECs). Multi-omic profiling and functional transport assays showed that iCE-BECs have a brain endothelial gene signature and recapitulate receptor-mediated transcytosis of a clinically validated BrainshuttleTM antibody against transferrin receptor. Engineered iCE-BECs homozygous for ApoE4 had altered spatiotemporal organization of early endosomes, increased transferrin receptor expression and reduced cytoplasmic iron. Our data revealed that ApoE4 can impact intracellular transport and iron homeostasis at the BBB in a cell-autonomous manner. This finding could be relevant for the brain delivery of therapeutic antibodies for Alzheimers disease.

cell biology↗

bioRxiv2021

Androglobin, a chimeric mammalian globin, is required for male fertility

Spermatogenesis is a highly specialised process, involving multiple dedicated pathways and regulatory check-points. Defects ultimately lead to male sub-fertility or sterility, and numerous aspects of mammalian sperm formation remain unknown. The predominant expression of the latest globin family member, androglobin (Adgb) in mammalian testis tissue prompted us to assess its physiological function in spermatogenesis. Adgb knockout mice display male infertility, reduced testis weight, impaired maturation of elongating spermatids, abnormal sperm shape and ultrastructural defects in microtubule and mitochondrial organisation. Epididymal sperm from Adgb knockout animals display multiple flagellar malformations including coiled, bifide or shortened flagella, and erratic acrosomal development. Following immunoprecipitation and mass spectrometry, we could identify septin 10 (Sept10) as interactor of Adgb. The Sept10-Adgb interaction was confirmed both in vivo using testis lysates, and in vitro by reciprocal co-immunoprecipitation experiments. Furthermore, absence of Adgb leads to mislocalisation of Sept10 in sperm, indicating defective manchette and sperm annulus formation. Finally, in vitro data suggest that Adgb contributes to Sept10 proteolysis in a calmodulin (CaM)-dependent manner. Collectively, our results provide evidence that Adgb is essential for murine spermatogenesis and further suggest that interdependence between Adgb and Sept10 is required for sperm head shaping via the manchette and proper flagellum formation.

developmental biology↗

bioRxiv2021

Albendazole reduces endoplasmic reticulum stress induced by Echinococcus multilocularis in mice

BackgroundEchinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with relatively frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice. MethodsE. multilocularis- and mock-infected C57BL/6 mice were subdivided six weeks after infection into vehicle and albendazole (ABZ) treated groups. Eight weeks later, liver tissue was collected to examine mRNA, microRNA (miR) and protein expression of UPR- and ERS-related genes. ResultsE. multilocularis infection upregulated UPR- and ERS-related proteins, including ATF6, CHOP, GRP78, ERP72, H6PD and calreticulin, whilst PERK and its target eIF2 were not affected, and IRE1 and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed the increased ATF6 and calreticulin protein expression, tended to reverse increased CHOP, GRP78, ERP72 and H6PD expression, and decreased ATF4 and IRE1 expression to levels seen in mock-infected mice. The expression of miR-146a-5p (downregulated by IRE1) and miR-1839-5p (exhibiting a unique target site in the IRE1 3UTR) were significantly increased in E. multilocularis infected mice, an effect reversed by ABZ treatment. Other miRs analyzed were not altered in E. multilocularis infected mice. Conclusions and SignificanceAE causes UPR activation and ERS in mice. The E. multilocularis-induced ERS was ameliorated by ABZ treatment, indicating its effectiveness to inhibit parasite proliferation and downregulate its activity status. ABZ itself did not affect UPR in control mice. Identified miR-146a-5p and miR-1839-5p might represent biomarkers of E. multilocularis infection. Modulation of UPR and ERS, in addition to ABZ administration, could be exploited to treat E. multilocularis infection. Author summaryAlveolar echinococcosis is a zoonotic disease caused by the fox tapeworm Echinococcus multilocularis. Treatment of this fatal disease is limited to surgical intervention, preferably radical curative surgery if possible, and the use of parasitostatic benzimidazoles. It is not yet fully understood how the parasite can remain in the hosts tissue for prolonged periods, complicating the development of therapeutic applications. This work investigated an involvement of the unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection and upon treatment with albendazole (ABZ) in mice. The results revealed increased expression levels of the ERS sensor ATF6 and of downstream target genes in liver tissue of E. multilocularis- compared to mock-infected mice. Additionally, H6PD, generating NADPH within the endoplasmic reticulum, and the lectin-chaperone calreticulin were increased in E. multilocularis infected liver tissue while the expression of the ERS associated genes ATF4 and IRE1 were decreased. The miR-1839-5p and miR-146-p, linked to IRE1, were elevated upon E. multilocularis infection, offering potential as novel biomarkers of alveolar echinococcosis. The observed gene expression changes were at least partially reversed by ABZ treatment. Whether modulation of UPR and ERS targets can improve the therapy of alveolar echinococcosis remains to be investigated.

pathology↗

bioRxiv2021

Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males

BackgroundSteroid 5{beta}-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. MethodsAkr1d1-/-mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/-mice were challenged with a 60% high fat diet. ResultsAkr1d1-/-mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/-mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/-mice were not protected against diet induced obesity and insulin resistance. ConclusionThis study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.

physiology↗

bioRxiv2020

Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Natures treasures, however, could be used more effectively. Yet, reliable pipelines for large scale target prediction of natural products are still rare. We have developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs) - a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17{beta}-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target prediction and guidance on using the respective tools.

bioinformatics↗