Biology subjects

Koster, M. H.

Publications and source records attributed to Koster, M. H..

5 recordsLinked to original sources

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↗

bioRxiv2022

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T-cells accumulate cholesterol, which could lead to a pro-inflammatory phenotype. However, the role of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) in T-cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generated mice with T-cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T-cell Abca1/Abcg1-deficiency decreased blood, lymph node, and splenic T-cells, and increased T-cell activation and apoptosis. T-cell Abca1/Abcg1-deficiency induced a premature T-cell aging phenotype in middle-aged (12-13 months) Ldlr-/- mice, reflected by upregulation of senescence markers. Despite T-cell senescence and enhanced T-cell activation, T-cell Abca1/Abcg1-deficiency decreased atherosclerosis and aortic inflammation in middle-aged Ldlr-/- mice, accompanied by decreased T-cells in atherosclerotic plaques. We attribute these effects to T-cell apoptosis downstream of T-cell activation. Collectively, T-cell cholesterol efflux pathways are critical for maintaining T-cell numbers, suppress senescence, and induce atherosclerosis in middle-aged Ldlr-/- mice.

immunology↗

bioRxiv2021

Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.

cancer biology↗

bioRxiv2021

Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

In age-related neurodegenerative disease, like Alzheimers and Parkinsons disease, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm- and human cell models for disease. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated SERF2 brain-specific knockout mice which, unlike full body knockout mice, were viable, and showed no major behavioral and cognitive abnormalities. We combined these knockout mice with the APPPS1 mouse model for human amyloid beta aggregation. Using structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in human brain, we show that knockout of SERF2 alters the structure of amyloid fibrils and deposits. Moreover, scanning transmission electron microscopy revealed thicker, shorter and more densely packed amyloid in absence of SERF2. Altogether, our data reveal pleiotropic functions of SERF in development and aging and support a function as a modifier of amyloid aggregation in mammalian brain. Our results indicate that single cellular factors like SERF can determine the structural outcome of amyloid aggregation, offering possibilities for polymorphism-based disease interventions.

molecular biology↗

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↗