Biology subjects

Ravnskjaer, K.

Publications and source records attributed to Ravnskjaer, K..

4 recordsLinked to original sources

bioRxiv2025

Adipose tissue cell states linked to progression and clinical subtypes of MASLD in human obesity

Adipose tissue dysfunction is a key determinant of inter-individual variability in obesity-associated comorbidities, yet the underlying tissue-level mechanisms linking adipose remodeling to progression of metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. We applied single-nucleus RNA sequencing to abdominal subcutaneous adipose tissue (SAT) from individuals with severe obesity, stratified by histologically defined MASLD stage, and integrated these data with bulk RNA-seq from [~]200 individuals. MASLD was associated with adipocyte hypertrophy and near-depletion of an ADH1BHI adipocyte subset linked to improved lipid buffering and systemic metabolic health. Conversely, lipid-associated macrophages (LAMs) expanded in MASLD, coordinating lipid-handling and inflammatory programs in the myeloid compartment. In advanced metabolic dysfunction-associated steatohepatitis (MASH), we identified a senescence-associated PLAUHI progenitor subpopulation with pro-inflammatory signaling potential. Whereas LAMs were broadly enriched in MASLD subtypes, PLAUHI progenitors specifically marked a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight cellular remodeling of adipose tissue as a potential driver of MASLD heterogeneity and progression.

cell biology↗

bioRxiv2025

PAF15-PCNA assembly exhaustion governs lagging strand replication and replisome integrity

Genome replication in eukaryotic cells is surveyed by the S-phase checkpoint, which orchestrates sequential replication origin activation to avoid exhaustion of hitherto poorly defined rate-limiting replisome components. Here, we find that excessive activation of replication origins depletes chromatin-bound PCNA and lagging strand components, thereby limiting additional PCNA loading at new origins when checkpoint control is disrupted. PAF15 (PCNA-associated factor 15) emerges as a dosage-sensitive regulator of PCNA, delineating the dynamic range of global genome duplication and defining distinct roles for PCNA on the leading and lagging strands. Through its high-affinity PIP motif and interaction within the DNA encircling channel of PCNA, PAF15 stabilizes PCNA exclusively on the lagging strand, optimizing and rate-limiting lagging strand processing. On the other hand, misregulation of PAF15--whether by overexpression or mislocalization to the leading strand--impairs replication fork progression and leads to cell death. These defects are mitigated by TIMELESS and CLASPIN, which restrain PAF15-PCNA interactions beyond the lagging strand. E2F4-mediated repression orchestrates PAF15 expression in normal and cancer cells, maintaining its optimal dosage for lagging strand-specific interactions with PCNA. Thus, the S-phase checkpoint functions in concert to restrict origin activation when lagging strand PAF15-PCNA assembly is exhausted, linking a previously concealed strand-specific rate limitation to overall replication dynamics.

biochemistry↗

bioRxiv2024

Laser speckle imaging of hepatic microcirculation

The liver controls blood homeostasis and depends critically on adequate blood supply. While the global regulation of liver blood flow via the hepatic arterial buffer response is well established, the mechanisms governing hepatic sinusoidal hemodynamics remain elusive. We use laser speckle contrast imaging to investigate the hepatic microvascular blood flow in anesthetized rats. Laser speckle contrast imaging offers a spatial resolution of a few micrometers, enabling visualization of individual microvessels, and a temporal resolution sufficient to track flow dynamics. This allowed us to resolve individual sinusoids and venules on the liver surface and to detect a reduction of the blood flow following local Angiotensin-II injections. We show that the blood flow oscillates with frequencies within the range of 0.05-0.4 Hz, which may be linked to rhythmic contraction of upstream blood vessels. Our findings provide insights into vessel-specific liver microcirculation in vivo, offering new opportunities to explore vascular dysfunction mechanisms in metabolic liver diseases.

physiology↗

bioRxiv2024

Deep Proteome Profiling of Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers. Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT). In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicate liver endothelial and hepatic stellate cells as main source of the ECM rearrangements, and hepatocytes as the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins that correlate with their expression in WAT rather than liver yet could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models consistently outperform existing methods for predicting MASLD and liver fibrosis from human blood samples.

systems biology↗