Alaa Othman

Last Name

Othman

First Name

Alaa

ORCID

0000-0002-0092-5594

Organisational unit

06238 - Metabolomics/Biophysics (FGCZ) / Metabolomics/Biophysics (FGCZ)

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Publications 1 - 10 of 27

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men
Maushart, Claudia Irene; Sun, Wenfei; Othman, Alaa; et al. (2023)
eBioMedicine
Background Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans.Methods We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.gov NCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed.Findings Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments.Interpretation Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes.
Circulating extracellular vesicles can transport stress signals to the male germline
Alshanbayeva, Anar; Steg, Leonard C.; Othman, Alaa; et al. (2025)
bioRxiv
Extracellular vesicles (EVs) play a key role in cell-cell communication by transporting bioactive molecules from donor to recipient cells across the body. While their involvement in somatic cells communication is well described, somatic-to-germ cells communication remains understudied. We show that small EVs (sEVs) can vehicle signals of early life stress (ELS) from circulation to sperm consequentially for the offspring. In mice, ELS persistently modifies RNA, lipids and metabolites in plasma sEVs. Chronic injection of plasma sEVs from ELS-exposed males alters the sperm transcriptome and is reflected in the transcriptome of embryos. This leads to metabolic dysfunctions in the adult offspring. These findings highlight a role of circulating sEVs in soma-to-germline communication relevant for the intergenerational transmission of ELS effects.
Optimisation of electron-induced dissociation parameters for molecular annotation of glycerides and phospholipids in fast LC-MS
Wu , Vincen; Moyal , Abraham; Othman, Alaa; et al. (2025)
The Analyst
Electron-induced dissociation methods, particularly electron impact excitation of ions from organics (EIEIO), offer enhanced capabilities for lipid structural elucidation over traditional collision-induced dissociation (CID). Despite their analytical promise, the practicality of EIEIO within routine liquid chromatography-mass spectrometry (LC-MS) workflows remains largely unexplored. In this study, we optimised LC-EIEIO-MS analysis for the rapid and detailed structural annotation of glycerides and phospholipids. We evaluated the effects of reaction times, accumulation times, and electron kinetic energies using lipid standards from multiple classes and at varying concentrations. Our results revealed that short reaction times of 30 ms consistently yielded stronger diagnostic signals crucial for lipid class identification and sn-position discrimination at concentrations as low as 200 pg on column. To systematically infer the position of double bonds from EIEIO spectra, we introduced LipidOracle, a software that tests all possible isomers and correctly accounts for missing data, noise, and crowded spectra. We demonstrated that longer accumulation times of 200 ms were most effective for determining carbon-carbon double bond (C C) positions, particularly in polyunsaturated lipids. Finally, we evaluated the performance of EIEIO with liver and plasma extracts. Overall, we demonstrate that comprehensive lipid structural characterisation, including sn-position and double bond locations in fatty acyl chains, is achievable within typical LC-MS timescales ( 0.2 s). Our findings outline practical guidelines for high-throughput analysis of complex lipid samples by EIEIO.
The molecular signature of heat stress in sweat reveals non-invasive biomarker candidates for health monitoring
Brasier, Noé Karl; Niederberger, Carmela; Zanella, Martina; et al. (2025)
Communications Biology
Heat stress is a significant public health challenge that leads to an increased risk of serious health deterioration, injuries, and loss of economic productivity. While the gold standard for monitoring heat stress continues to remain with population-based measurements, a straight-forward person-centered approach is lacking. Sweat can supply a wealth of molecular information, ranging from protein levels to levels of metabolites; it is thus a promising monitoring biofluid. A thorough investigation of sweat’s molecular signature during heat stress is called for. We conducted a cross-over study on healthy participants with personalized heat-stress visits to investigate heat stress’s proteomic and molecular signatures in sweat. Through mass-spectrometry analysis, we identified multiple candidate biomarkers ranging from amino acids to microbiome metabolites and proteins. To the best of our knowledge, these biomarker candidates represent the first successful approach to metabolically differentiate between various heat stressors thereby enabling their acute monitoring. While these biomarker candidates need further investigation to confirm their clinical value, many have already been identified as directly associated with heat stress in animals and plants. Once further investigated, next-generation wearable devices for person-centered, on-skin sweat-analysing platforms could be developed that would transform health management during exposure to heat stress.
Basal re-esterification finetunes mitochondrial fatty acid utilization
Sharma, Anand Kumar; Wang, Tongtong; Othman, Alaa; et al. (2023)
Molecular Metabolism
Objective: Emerging evidence suggest the existence of constant basal lipolysis and re-esterification of a substantial fraction of thus liberated fatty acids. In stimulated lipolysis, the re-esterification is proposed to be a protective mechanism against lipotoxicity; however, the role of the lipolysis coupled to re-esterification under basal conditions has not been deciphered. Methods: We used adipocytes (in vitro differentiated brown and white adipocytes derived from a cell line or primary SVF culture) to study the effect of inhibition of re-esterification by pharmacological DGAT1 and DGAT2 inhibitors alone or in combination. We then evaluated cellular energetics, lipolysis flux, and lipidomic parameters along with mitochondrial properties and fuel utilization. Results: In adipocytes, DGAT1 and 2 mediated re-esterification is a moderator of fatty acid oxidation. Combined inhibition of both DGATs (D1+2i) increases oxygen consumption, which is largely due to enhanced mitochondrial respiration by lipolysis-derived fatty acids (FAs). Acute D1+2i selectively affects mitochondrial respiration without affecting the transcriptional homeostasis of genes relevant to mitochondrial health and lipid metabolism. D1+2i enhances the mitochondrial import of pyruvate and activates AMP Kinase to counteract CPT1 antagonism, thus facilitating the mitochondrial import of fatty acyl-CoA. Conclusions: These data implicate the process of re-esterification in the regulation of mitochondrial FA usage and uncover a mechanism of FAO regulation via crosstalk with FA re-esterification.
High-Throughput RPLC-MS/MS Quantification of Short- and Medium-Chain Fatty Acids
Schauer, Stefan; Othman, Alaa (2025)
Methods in Molecular Biology ~ Clinical Metabolomics
Short- and medium-chain fatty acids (SMCFA) are monocarboxylic acids with a carbon chain length of 1–12 carbon atoms. They are mainly produced in humans by the gut microbiota, play crucial metabolic roles, are vital for intestinal health, and have multifaceted impact on immune and neurological functions. Accurate detection and quantification of SMCFA in different human biofluids is achieved using 3-nitro phenylhydrazine (3-NPH) derivatization of the free fatty acids followed by reverse phase liquid chromatography (RPLC) separation and detection by tandem mass spectrometry (MS/MS). Here, we describe the simultaneous measurement of 14 SMCFA and lactate in detail. All 3-NPH-SMCFA-hydrazones are separated in less than 5 min with an 8-min total run time (injection-to-injection). Linear dynamic range over 0.1–500 μM is achieved for most SCFAs, while it is 0.05–100 μM for MCFAs. Validation of the procedure depicts good linearity (R2 > 0.98) and repeatability (CV ≤ 20%). The lower limit of detection (LLOD) is 10–30 nM. The lower limit of quantification (LLOQ) is 50–100 nM for most analytes, while it is 0.5 μM for acetate. In conclusion, the method offers several benefits compared to alternative methods regarding throughput, selectivity, sensitivity, and robustness.
Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids
Othman, Alaa; Liu, Mingxia; Bode, Heiko; et al. (2023)
Frontiers in Physiology
ATP binding cassette transporter A1 (ABCA1) limits the formation of high density lipoproteins (HDL) as genetic loss of ABCA1 function causes virtual HDL deficiency in patients with Tangier disease. Mice with a hepatocyte-specific ABCA1 knockout (Abca1 HSKO) have 20% of wild type (WT) plasma HDL-cholesterol levels, suggesting a major contribution of hepatic ABCA1 to the HDL phenotype. Whether plasma sphingolipids are reduced in Tangier disease and to what extent hepatic ABCA1 contributes to plasma sphingolipid (SL) levels is unknown. Here, we report a drastic reduction of total SL levels in plasma of a Tangier patient with compound heterozygosity for mutations in ABCA1. Compared to mutation-free controls, heterozygous mutations in ABCA1 had no significant effect on total SLs in plasma; however, apoB-depleted plasma showed a reduction in total SL also in het carriers. Similarly, liver specific Abca1 KO mice (Abca1 HSKO) showed reduced total sphingolipids in plasma and liver. In parallel, apoM and sphingosine-1-phosphate (S1P) levels were reduced in plasma of Abca1 HSKO mice. Primary hepatocytes from Abca1 HSKO mice showed a modest, but significant reduction in total SLs concentration compared to WT hepatocytes, although SL de novo synthesis and secretion were slightly increased in Abca1 HSKO hepatocytes. We conclude that hepatic ABCA1 is a signficant contributor to maintaining total plasma pool of HDL sphingolipids, including sphingomyelins and S1P.
Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells
Colucci, Manuel; Zumerle, Sara; Bressan, Silvia; et al. (2024)
Cancer Cell
Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in “immunologically cold” tumors.
The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes
Rhein, Sina; Costalunga, Riccardo; Inderhees, Julica; et al. (2024)
Nature Communications
Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε−3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
NPC1 links cholesterol trafficking to microglial morphology via the gastrosome
Zareba, Joanna; Cattaneo, Elena F.; Villani, Ambra; et al. (2024)
Nature Communications
Microglia play important roles in brain development and homeostasis by removing dying neurons through efferocytosis. Morphological changes in microglia are hallmarks of many neurodegenerative conditions, such as Niemann-Pick disease type C. Here, NPC1 loss causes microglia to shift from a branched to an ameboid form, though the cellular basis and functional impact of this change remain unclear. Using zebrafish, we show that NPC1 deficiency causes an efferocytosis-dependent expansion of the microglial gastrosome, a collection point for engulfed material. In vivo and in vitro experiments on microglia and mammalian macrophages demonstrate that NPC1 localizes to the gastrosome, and its absence leads to cholesterol accumulation in this compartment. NPC1 loss and neuronal cell death synergistically affect gastrosome size and cell shape, increasing the sensitivity of NPC1-deficient cells to neuronal cell death. Finally, we demonstrate conservation of cholesterol accumulation and gastrosome expansion in NPC patient-derived fibroblasts, offering an interesting target for further disease investigation.

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Alaa Othman

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