Biology subjects

Gurzov, E. N.

Publications and source records attributed to Gurzov, E. N..

7 recordsLinked to original sources

bioRxiv2026

PTPRF is a stress responsive cytoskeletal checkpoint that coordinates metabolic adaptation in hepatocytes and β cells

Cytoskeletal remodeling is essential for adaptation to nutrient availability, yet how cells coordinate actin dynamics with glucose homeostasis in metabolic organs remains unclear. Here, we identify a pathway linking metabolic stress to actin reorganization in hepatocytes and pancreatic {beta} cells. This mechanism involves transcriptional repression of the receptor protein tyrosine phosphatase PTPRF by spliced XBP1, a key unfolded protein response factor. In hepatocytes, PTPRF loss under dietary stress enhances insulin signaling, increases mitochondrial respiration and reduces steatosis. Proteomic analyses show that PTPRF interacts with regulators of actin polymerization and cell junctions, and its deletion promotes actin filament organization, shifting metabolism toward oxidative pathways. In {beta} cells, PTPRF deficiency similarly enhances actin polymerization and augments glucose-stimulated insulin secretion in obesity. Collectively, these findings place PTPRF as a nutrient-responsive regulator of cytoskeletal remodeling that coordinates hepatic metabolism and {beta}-cell function, highlighting its potential as a therapeutic target for improving systemic glucose control.

physiology↗

bioRxiv2026

Loss of PTPRK in hepatocytes reduces steatosis and carcinogen-induced tumour development in obesity

Protein tyrosine phosphatases are crucial regulators of metabolism with specific roles in different tissues. To investigate hepatocyte-specific function of protein tyrosine phosphatase receptor type K (PTPRK), we generated mice carrying floxed Ptprk alleles and crossed them with Alb-Cre mice (Ptprk{Delta}Hep mice). Under chow feeding, Ptprk{Delta}Hepmice were largely comparable to littermate controls. In contrast, Ptprk{Delta}Hepmice fed a high-fat, high-fructose, high-cholesterol diet exhibited reduced steatosis, lower hepatic PPAR{gamma}, and blunted hepatocyte hypertrophy, accompanied by improved systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps. We identified PTPRK-interacting proteins enriched for metabolic functions associated with glycolysis and lipid biosynthesis using pull downs from primary hepatocyte lysates. In line with these findings, Ptprk{Delta}Hep mice developed fewer tumours than controls in an obesity and carcinogen-induced hepatocellular carcinoma (HCC) model. Our data show that under nutrient excess PTPRK is functionally engaged in hepatocytes to support PPAR{gamma}-linked steatotic growth, insulin resistance, and tumour initiation, highlighting PTPRK as a potential therapeutic target in MASLD-associated HCC.

pathology↗

bioRxiv2025

CellCousin2: An Optimized System for Partial Ablation and Tracing of Regenerative Lineages

Regeneration can rely on multiple cellular sources, including stem cells, self-duplicating cells, and transdifferentiating cells. A central question in regenerative biology is how these distinct lineages contribute to repair and interact within a functional regenerate. We previously developed the CellCousin system to study hcellular plasticity using inducible recombination and nitroreductase-mediated ablation in zebrafish. Here, we present CellCousin2, which introduces two key improvements for long-term tracking of spared and regenerating cells. First, to reduce background recombination, we developed a Dihydrofolate Reductase (DHFR)-CreER system with dual control: DHFR- mediated degradation in the absence of trimethoprim, and tamoxifen-dependent activation. This combination minimizes leakiness while maintaining high recombination efficiency. Second, we replaced the original nitroreductase with NTR2.0, enabling effective ablation with tenfold lower metronidazole concentration, reducing off-target effects on the liver. Together, these enhancements make CellCousin2 a robust platform for dissecting the dynamics and interactions of regenerative lineages.

developmental biology↗

bioRxiv2025

Feeding induces c-Fos in hepatocytes contributing to hepatocellular carcinoma in obesity

The transcription factor c-Fos plays an important role in hepatic metabolism; however, its role in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) is unclear. Here, we show that hepatic c-Fos is induced by insulin after feeding and suppressed by glucagon during fasting in chow-fed mice. In lean mice, adenovirus-mediated c-Fos ectopic expression in the liver is sufficient to cause insulin resistance. In diet-induced obesity or after ectopic expression in hepatocytes, c-Fos promotes MASLD progression by altering PPAR signaling and fatty acid metabolism pathways. Mechanistically, c-Fos drives glycolysis, stress-associated MAPK, and insulin-related PI3K-Akt signaling, exacerbating metabolic dysregulation. In HCC, c-Fos expression correlates with PI3K-Akt, MAPK, and calcium signaling pathways activation. Moreover, c-Fos siRNA knockdown in human liver cancer cells reduces proliferation and increases apoptosis under lipotoxic or ER stress conditions. These findings identify c-Fos as a critical mediator of liver steatosis progression, linking hepatocyte signaling and metabolic reprogramming to liver dysfunction and tumorigenesis.

cancer biology↗

bioRxiv2025

Volumetric imaging and single-cell RNAseq atlases identify cellular mechanisms of human dental pulp response during tooth decay progression

Dental pulp responses to dental decay, the most prevalent chronic disease worldwide, involve remodeling processes similar to those observed in other human pathological conditions. By integrating volumetric imaging and single-cell analysis across different disease stages in human samples, we uncovered the natural history of dental pulp responses to decay. At early stages, we observed an arterialization of the capillary networks and progressive outward remodeling of the larger vessels. Neurogenesis of nerve endings and the reprogramming of perivascular progenitor cells into fibroblasts are also observed, initiating the physiological reparative response of the stroma. Pathological angiogenesis and nerve regression combined with dental pulp fibrosis at later stages of tooth decay determine irreversible pulpitis. These results provide a basis for understanding dental tissue response to injury, driving a paradigm shift in patient management. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/653296v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@15d1d86org.highwire.dtl.DTLVardef@3d556corg.highwire.dtl.DTLVardef@b33e32org.highwire.dtl.DTLVardef@1b84a1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish

The livers regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two new partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.

developmental biology↗

bioRxiv2023

Protein tyrosine phosphatase receptor kappa regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and positively correlated with PPAR{gamma}-induced lipogenic signalling. High-fat-fed PTPRK knockout mice displayed reduced weight gain and hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis. Our study defines a novel role for PTPRK in regulating hepatic glycolysis, lipid metabolism, and tumour development. PTPRK inhibition may provide therapeutic possibilities in obesity-associated liver diseases. HighlightsO_LIHepatic receptor-type PTPs are increased in MASLD C_LIO_LIPTPRK is expressed in hepatocytes and upregulated in obesity C_LIO_LIPTPRK deficiency reduces body fat mass and liver steatosis in diet-induced obesity C_LIO_LIPTPRK regulates hepatic glycolysis and lipogenesis, promoting tumorigenesis C_LI

cancer biology↗