Biology subjects

Kuipers, F.

Publications and source records attributed to Kuipers, F..

7 recordsLinked to original sources

bioRxiv2025

Condensate-Driven Triglyceride Depletion Links α-Synuclein to Mitochondrial Dysfunction

Inclusions of -Synuclein (Syn) characterize multiple age-related neurodegenerative diseases, including Parkinsons disease (PD) and Multiple System Atrophy (MSA). While interactions between Syn and lipids are known to contribute to Syn pathobiology, the precise cellular mechanisms that link lipids to Syn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we found that Syn progressively alters lipid metabolism in aging worms. Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on Syns properties to condensate and form inclusions. Apart from lowering TAG levels, Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates Syn-induced loss of C. elegans motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the Syn-impaired mitochondrial response and rescues motility. These results link Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate Syn-induced toxicity in Parkinsons and other age-related synucleinopathies.

cell biology↗

bioRxiv2023

Mother-Infant Gut Viruses and their Bacterial Hosts: Transmission Patterns and Dynamics during Pregnancy and Early Life

Early development of the gut ecosystem is crucial for lifelong health. While infant gut bacterial communities have been studied extensively, the infant gut virome remains under-explored. We longitudinally assessed the composition of gut viruses and their bacterial hosts in 322 total metagenomes and 205 metaviromes from 30 mothers during and after pregnancy and from their 32 infants during their first year of life. While the maternal gut virome composition remained stable during late pregnancy and after birth, the infant gut virome was dynamic in the first year of life and contained a higher abundance of active temperate phages compared to the maternal gut viromes. The infant gut virome composition was also influenced by infant feeding mode and place of delivery. Lastly, we provide evidence of viral-bacterial strains co-transmission from mothers to infants, demonstrating that infants acquire some of their virome from their mothers gut. Highlights- Longitudinal characterisation of the gut microbiome and virome in 30 mothers during pregnancy, at birth and 3 months after birth and in 32 infants from birth across the first year of life. - The maternal gut bacteriome changes from the first to the second trimester and then remains stable through birth and the first 3 months after birth. - The maternal gut virome remains stable during late pregnancy, birth and the first 3 months after birth. - The infant gut virome is highly dynamic during the first year of life and is shaped by infant feeding mode and place of delivery. - The infant gut harbours more temperate bacteriophages than the maternal gut, but their relative abundance decreases with increasing infant age. - Gut viral strains and their bacterial host strains are co-transmitted from mothers to their infants. - Gut viral strains are transferred from mother to infant around birth directly or via transfer of their bacterial hosts followed by the induction of prophages.

microbiology↗

bioRxiv2023

Dietary cystine restriction increases the proliferative capacity of the small intestine of mice

Over 88 million people are currently estimated to have adopted towards a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine concentrations. Sufficient uptake of cysteine is crucial, as it serves as substrate for protein synthesis and conversion to taurine and glutathione. In this study, we therefore investigate the effect of low dietary cystine, the oxidized derivative of cysteine, on intestinal epithelial layer function. Mice (8/group) received a high fat diet with normal or low cystine concentration for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels after 2 weeks. Stem cell markers as well as the proliferation marker Ki67 were increased upon cystine restriction in the small intestine. In line with this, gene set enrichment analysis indicated enrichment of Wnt signaling in the small intestine of mice on the low cystine diet, indicative of proliferative cells. Increased proliferation was absent in the colon. In the colon, dietary cystine restriction results in an increase in goblet cells, but no significant changes in the thickness of the mucus barrier or in its protective capacity. Also the microbiome was not changed upon dietary restriction. In conclusion, we show that cystine restriction for two weeks does not seem to induce any systemic effects. The increased proliferative capacity and number of goblet cells observed in the intestine may be the effect of starting epithelial damage or a reaction of the epithelium to start enlarging the absorptive capacity.

molecular biology↗

bioRxiv2023

The endosomal sorting complex Retromer has a central role insystemic cholesterol homeostasis by controlling endo-lysosomal cholesterol transport in hepatocytes

BackgroundDisturbed hepatic cholesterol homeostasis is associated with multiple diseases, including atherosclerotic cardiovascular disease and metabolic dysfunction- associated steatotic liver disease. The endo-lysosomal system is essential for cholesterol uptake and intracellular distribution, yet the mechanisms governing these processes remain incompletely understood. Here, we investigated the impact of hepatic VPS35, a subunit of the endosomal sorting complex retromer, on hepatocellular and whole-body cholesterol homeostasis. MethodsWe generated a liver-specific Vps35 knockout mouse model (Vps35HepKO) and applied biochemical analyses, proteomics, and stable-isotope-labeled tracers to quantify critical processes of cholesterol metabolism. Human iPSC-derived liver organoids and CRISPR technology were used to translate our findings to humans. Mechanistic studies were performed in precision-cut liver slices from WT and Vps35HepKO mice. ResultsHepatic VPS35 deficiency led to an increase in endo-lysosomal degradative compartments and a marked reduction in specific lysosomal proteins, including lysosomal acid lipase (LAL), Scavenger Receptor Class B Member 2 (SCARB2), and Niemann-Pick type C1 (NPC1). Using pathway-specific inhibitors, we showed that VPS35 loss impairs the translation of SCABR2 and NPC1. Consistently, human iPSC-derived liver organoids lacking VPS35 also exhibited reduced expression of NPC1 and SCARB2 proteins. The decrease in these lysosomal proteins correlated with increased cholesterol levels in the plasma and liver of Vps35HepKO mice. This was likely explained by the disrupted cholesterol trafficking through the endo-lysosomal system, delayed plasma cholesterol turnover, and upregulated cholesterol biosynthesis. ConclusionThese findings uncover a previously unknown role for the hepatic retromer complex in maintaining systemic cholesterol homeostasis. Beyond its established function in endosomal cargo transport, we now demonstrate that retromer is also essential for lysosomal cholesterol handling. This role is mediated by regulating key lysosomal proteins involved in cholesterol metabolism, including LAL, NPC1, and SCARB2.

molecular biology↗

bioRxiv2021

Gut microbial structural variations as determinants of human bile acid metabolism

Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host{square}gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but how the highly variable genomes of gut bacteria interact with host BA metabolism remains largely unknown. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two Dutch cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete subspecies showed correlations with BA metabolism. Metagenome-wide association analysis identified 797 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the first large-scale microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.

microbiology↗

bioRxiv2020

Dynamic binning peak detection and assessment of various lipidomics liquid chromatography-mass spectrometry pre-processing platforms

Liquid chromatography-mass spectrometry (LC-MS) based lipidomics generate a large dataset, which requires high-performance data pre-processing tools for their interpretation such as XCMS, mzMine and Progenesis. These pre-processing tools rely heavily on accurate peak detection, which depends on setting the peak detection mass tolerance (PDMT) properly. The PDMT is usually set with a fixed value in either ppm or Da units. However, this fixed value may result in duplicates or missed peak detection. Therefore, we developed the dynamic binning method for accurate peak detection, which takes into account the peak broadening described by well-known physics laws of ion separation and set dynamically the value of PDMT as a function of m/z. Namely, in our method, the PDMT is proportional to [Formula] for FTICR, to [Formula] for Orbitrap, to m/z for Q-TOF and is a constant for Quadrupole mass analyzer, respectively. The dynamic binning method was implemented in XCMS [1,2] and the adopted source code is available in the Appendix. Our further goal was to compare the performance of different lipidomics pre-processing tools to find differential compounds. We have generated set samples with 43 lipids internal standards differentially spiked to aliquots of one human plasma lipid sample using Orbitrap LC-MS/MS. The performance of the various pipelines using aligned parameter sets was quantified by a quality score system which reflects the ability of a pre-processing pipeline to detect differential peaks spiked at various concentration levels. The quality score indicates that the dynamic binning method improves the performance of XCMS (maximum p-value 9.8{middle dot}10-3 of two-sample Wilcoxon test). The modified XCMS software was further compared with mzMine and Progenesis. The results showed that modified XCMS and Progenesis had a similarly good performance in the aspect of finding differential compounds. In addition, Progenesis shows lower variability as indicated by lower CVs, followed by XCMS and mzMine. The lower variability of Progenesis improve the quantification, however, provide an incorrect quantification abundance order of spiked-in internal standards.

biochemistry↗

bioRxiv2020

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet

Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype.

pathology↗